Glucokinase activators and pharmaceutical compositions containing the same as an active ingredient

ABSTRACT

The present invention relates to new compounds of formula (1) exhibiting excellent activity for glucokinase, and pharmaceutical compositions comprising the same as an active ingredient.

TECHNICAL FIELD

The present invention relates to new compounds exhibiting excellentactivity for glucokinase (glucokinase activators, GKAs), andpharmaceutical compositions comprising the same as an active ingredient.

BACKGROUND ART

Diabetes affects harmful influences on human health, causing variouscomplications. Diabetes may be classified into type 1 diabetes whereinsulin is not excreted due to the destruction of pancreatic cells, andtype 2 diabetes where insulin is not produced due to the otherconditions or the body does not response to insulin. The type 2 diabetesoccupies 90% or more of the total patients suffered from diabetes.Typical complications accompanied with diabetes include hyperlipidemia,hypertension, retinosis, renal failure, etc. (Zimmer P., et al., Nature,2001, 414, 782). As the therapeutic agents for diabetes, sulfonyl ureas(facilitating insulin secretion in the pancreatic cells), biguanides(suppressing glucose production in the liver), α-glucosidase inhibitors(suppressing glucose uptake in the bowels), etc. are used, among whichperoxisome proliferator-activated receptor gamma (PPAR γ) agonists(thiazolidinediones, increased insulin sensitivity) are recentlyfocused. However, these agents show some side effects, such as weightgain, according to the respective mechanisms of action (Moller D. E.,Nature, 2001, 414, 821). Thus, there has been a need for the developmentof an agent for the treatment of diabetes, which does not cause suchside effects.

For a normal healthy person, blood glucose is accurately controlledwithin a safe and narrow physiological range by means of variousendocrine glucostatic systems. If such glucostatic systems do not work,glucose intolerance occurs first, which is gradually grown to the type 2diabetes. Dysfunction of such control mechanism is resulted from (i)decrease of secretion of insulin from the pancreatic cells, (ii)increases of insulin resistance in the liver, cells of adipose tissue,and cells of skeletal muscle, and (iii) excess production of bloodglucose by the liver.

According to many research outputs obtained during the past forty years,glucokinase that belongs to hexokinase IV series are involved in thefirst step of glucose metabolism to directly control the glucose contentin the blood, whereby it plays an important role in the maintenance ofglucose homeostasis in the body.

The glucokinase in the pancreatic cells can determine the thresholds ofglucose-stimulated insulin release (GSIR) by acting as a glucose sensor.The glucokinase decreases blood glucose by phosphorylating glucose intoglucose-6-phosphate consuming ATP, and keeping glucose-6-phosphate inthe cells (Meglasson M.D. and Matschinsky F. M., Diabetes Metab Rev,1986, 2, 163).

On the other hand, the glucokinase in hepatocytes has the feature ofbeing short-term controlled by glucokinase regulatory protein.Glucokinase regulatory protein forms a 1:1 complex with glucokinase, andacts as a “competitive inhibitor” against glucose to confine theinactivated glucokinase within the nucleus and to protect and stabilizeit from other proteins such as decomposition enzymes, etc. It has beenreported that fructose-6-phosphate further stabilizes glukinaseregulatory protein, whereas fructose-1-phosphate separates glucokinasefrom glucokinase regulatory protein and transfers it from nucleus tocytoplasm to keep its activated state (Van Schaftingen E., Eur JBiochem, 1989, 179). The glucokinase in hepatocytes appropriatelycontrols the glucose metabolism in the liver. That is, glucose uptakeand production are effectively controlled under the satiation or faststate (Agius L., et al., J Biol Chem, 1996, 271, 30479).

As explained above, glucokinase activates the two functions of (i)direct control of blood glucose in the liver, and (ii) facilitation ofinsulin secretion within the physiological range after detection ofglucose concentration in the pancreas, and thus, plays a very importantrole in the maintenance of glucose homeostasis.

The experimental results in many rodent models suggested thatglucokinase is a key regulator in the maintenance of glucosehomeostasis. Rats lacking the glucokinase gene function in pancreaticbeta cells show a significant hyperglycemic symptom, and rats lackingthe glucokinase gene function in hepatocytes show depressed glucoseuptake and hyperglycemic symptom. On the other hand, when theglucokinase gene is over expressed in hepatocytes of normal rats,amelioration effect of glucose tolerance is shown (Rossetti L., et al.,Am J Physiol, 1997, 273, E743). And, the over expression of glucokinasein diabetic rats induces amelioration of glucose tolerance and bloodglucose lowering effect under the fast state (Desai U. J., et al., Am JDiabetes, 2001, 50, 2285).

Hitherto, about 200 glucokinase gene mutants have been clinicallyreported for humans. Patients of MODY (maturity onset diabetes of theyoung)-2, a subtype of type 2 diabetes, showed some decrease ofglucokinase activity due to the loss-of-function mutation andhyperglycemia due to the decrease of insulin secretion. On the contrary,patients of PNDM (permanent neonatal diabetes) and PHHI (persistenthyperinsulinemia hypoglycemia of infancy) showed serious hypoglycemiadue to the glucokinase activation based on the gain-of-function mutation(Matsinsky F. M., et al., Frontiers in Daibetes, 2004, 16, chapter 4-7).Such phenotypes of glucokinase-associated diseases suggest thatglucokinase plays an important role in the maintenance of glucosehomeostasis in the body, which leaves a clue to develop a drug forenhancing the glucokinase activity.

According to the recent studies (Nakamura A., et al., Impact of smallmolecule glucokinase activator on glucose metabolism and beta cell mass,Endocrinology, 2008, Nov.), glucokinase activators facilitate pancreaticbeta cell division to improve the glucose metabolism by maintaining thepancreatic cell mass. Also, it has been reported that glucose metabolismand hyperglycemia can be normalized by the restoration of hepatocellularglucokinase activity only in 20 week old ZDF (Zucker diabetic fatty) ratmodel (Tones T. P., et al., Restoration of hepatic glucokinaseexpression corrects hepatic glucose flux and normalize plasma glucose inzucker diabetic fatty rats, 2008, Endocrinology, Oct.), which suggeststhat hepatocyte-specific glucokinase activators may be developed as atherapeutic agent that can be used for the type 1 diabetics as well asthe chronic type 2 diabetics in the future.

A lot of researches for glucokinase activators have been reported. Asthe recently published patents, WO2007/007910A1, WO2006/112549A 1,WO2007/031739, WO2007/037534, WO2007/043638, WO2007/028135,US20070099930, WO2007/041365, WO2007/051847, WO2007/053345,WO2007/007910, WO2006/049304, etc. may be mentioned.

The present inventors extensively studied glucokinase activators, and asa result have confirmed that the indole compounds of formula (1) areeffective as glucokinase activators. Thus, they completed the presentinvention that relates to glucokinase activators based on indolestructure.

DETAILED DESCRIPTION OF THE INVENTION Technical Subject to be Solved

The object of the present invention is to provide glucokinase activatorsof the indole compounds of formula (1). It is also another object of thepresent invention to provide a composition for the prevention ortreatment of diseases caused by the decline of glucokinase activity,which comprises said compounds as an active ingredient.

Means for Solving the Technical Subject

The present invention provides the compounds of the following formula(1):

in which

X represents O or NH,

n denotes a number of 0 to 3,

Y represents a direct bond, —(CH₂)_(p)O—, —(CH₂)_(q)—, or—(CH₂)_(q)SO₂—,

p denotes a number of 0 to 2,

q denotes a number of 1 to 3,

R1 represents hydrogen, —(CR4R5)_(p)-A-R6 or —(CR4R5)_(q)—R6,

p and q are as defined above,

R4 and R5 independently of one another represent hydrogen orC₁-C₅-alkyl,

A represents 6˜12 membered aryl or optionally oxo-containingC₃-C₈-cycloalkyl, or represents 3˜10 membered heterocyclyl or heteroaryleach of which has 1 to 3 hetero atoms selected from O, S, and N,

R6 represents hydrogen, hydroxy, halogen, nitro, C₁-C₆-alkylcarbonyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxycarbonyl or carboxy,

R2 represents hydrogen, nitro, halogen, C₁-C₆-alkyl or trifluoromethyl,represents 5˜12 membered heteroaryl or heterocyclyl each of which has 1to 3 hetero atoms selected from N and O, or represents optionallyC₁-C₆-alkylsulfonyl-substituted 6˜12 membered aryl,

R3 represents R7-X—B—X′—,

B represents a direct bond, or represents 3˜10 membered heterocyclyl orheteroaryl each of which optionally contains oxo, is optionally fused,and has 1 to 4 hetero atoms selected from N, O and S,

X and X′ independently of one another represent a direct bond, or areselected from the group consisting of —CO—, —(CH₂)_(q)—, —NR4C(O)—,—NR4-, —OC(O)—, —O—, —(CH₂)_(p)C(O)—, —(CH₂)_(p)O—, —(CH₂)_(p)NR4-,—C(O)NR4- and —S(O)_(r)—, wherein p and q are as defined above, rdenotes a number of 0 to 2, and R4 represents hydrogen or C₁-C₅-alkyl,

R7 represents hydrogen, hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy,halogeno-C₁-C₆-alkyl or C₃-C₆-cycloalkyl, represents 6˜12 membered aryl,or represents 4˜8 membered heteroaryl or heterocyclyl each of which has1 to 4 hetero atoms selected from N and O,

where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl maybe optionally substituted, and the substituents are one or more selectedfrom the group consisting of hydroxy, halogen, nitrile, amino,C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-alkyl,halogeno-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkoxy and oxo,pharmaceutically acceptable salts or isomers thereof.

In the above definitions for the compounds of formula (1), the term‘alkyl’ means an aliphatic hydrocarbon radical. Alkyl may be saturatedalkyl that does not comprise alkenyl or alkynyl moiety, or unsaturatedalkyl that comprises at least one alkenyl or alkynyl moiety. “Alkenyl”means a group containing at least one carbon-carbon double bond, and“alkynyl” means a group containing at least one carbon-carbon triplebond. Alkyl may be branched or straight-chain when used alone or in acomposite form such as alkoxy.

Alkyl group may have 1 to 20 carbon atoms unless otherwise defined.Alkyl group may be a medium sized alkyl having 1 to 10 carbon atoms.Otherwise, alkyl group may be a lower alkyl having 1 to 6 carbon atoms.Typical examples thereof include, but not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl,propenyl, butenyl, etc. For example, C₁-C₄-alkyl has 1 to 4 carbon atomsin the alkyl chain, and is selected from the group consisting of methyl,ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and t-butyl.

The term ‘alkoxy’ means an alkyloxy having 1 to 10 carbon atoms unlessotherwise defined.

The term ‘cycloalkyl’ means a saturated aliphatic 3˜10 membered cycleunless otherwise defined. Typical examples thereof include, but notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term ‘aryl’ includes at least one ring having covalent π electronsystem, for example, monocyclic or fused polycyclic (i.e., cycles thatshare the adjacent carbon atom pairs) group. In the presentspecification, aryl means an aromatic 4˜10 membered, preferably 6˜10membered, monocyclic or multicyclic ring including phenyl, naphthyl,etc., unless otherwise defined.

The term ‘heteroaryl’ means an aromatic 3˜10 membered, preferably 4˜8membered, more preferably 5˜6 membered cycle that has 1 to 3 heteroatoms selected from N, O and S, and may be fused with benzo or C₃-C₈cycloalkyl, unless otherwise defined. The monocyclic heteroarylincludes, but not limited to, thiazole, oxazole, thiophene, furan,pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole,triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine,pyrimidine, pyrazine and the like. The bicyclic heteroaryl includes, butnot limited to, indole, indoline, benzothiophene, benzofuran,benzimidazole, benzoxazole, benzisoxazole, benzthiazole,benzthiadiazole, benztriazole, quinoline, isoquinoline, purine,puropyridine and the like.

The term ‘heterocycle’ means a 3˜10 membered, preferably 4˜8 membered,more preferably 5˜6 membered cycle that has 1 to 3 hetero atoms selectedfrom N, and S, may be fused with benzo or C₃-C₈ cycloalkyl, and issaturated or contains 1 or 2 double bonds, unless otherwise defined. Theheterocycle includes, but not limited to, pyrroline, pyrrolidine,imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine,morpholine, thiomorpholine, piperazine, hydrofuran and the like.

Other terms and abbreviations in the present specification may beunderstood to have the meaning conventionally used in this field by askilled artisan, unless otherwise defined.

Preferred compounds among the compounds of formula (1) above are thosewherein

X represents O or NH,

n denotes a number of 0 to 3,

Y represents a direct bond, —(CH₂)_(p)O—, —(CH₂)_(q)—, or—(CH₂)_(q)SO₂—,

p denotes a number of 0 to 2,

q denotes a number of 1 to 3,

R1 represents —(CR4R5)_(p)-A-R6 or —(CR4R5)_(q)—R6,

p and q are as defined above,

R4 and R5 independently of one another represent hydrogen orC₁-C₅-alkyl,

A represents 6˜12 membered aryl or optionally oxo-containingC₃-C₇-cycloalkyl, or represents 4˜8 membered heterocyclyl or heteroaryleach of which has 1 to 3 hetero atoms selected from O, S, and N,

R6 represents hydrogen, hydroxy, halogen, nitro, C₁-C₆-alkylcarbonyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxycarbonyl or carboxy,

R2 represents hydrogen, halogen, C₁-C₆-alkyl or trifluoromethyl,represents 5˜8 membered heteroaryl or heterocyclyl each of which has 1to 3 hetero atoms selected from N and O, or represents optionallyC₁-C₆-alkylsulfonyl-substituted 6˜10 membered aryl,

R3 represents R7-X—B—X′—,

B represents a direct bond, or represents 4˜10 membered heterocyclyl orheteroaryl each of which optionally contains oxo, is optionally fused,and has 1 to 4 hetero atoms selected from N, O and S,

X and X′ independently of one another represent a direct bond, or areselected from the group consisting of —CO—, —(CH₂)_(q)—, —NR4C(O)—,—NR4-, —OC(O)—, —O—, —(CH₂)_(p)C(O)—, —C(O)NR4- and —S(O)_(r)—, whereinp and q are as defined above, r denotes a number of 0 to 2, and R4represents hydrogen or C₁-C₅-alkyl,

R7 represents hydrogen, hydroxy, C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl orC₃-C₆-cycloalkyl, represents 6˜12 membered aryl, or represents 4˜8membered heteroaryl or heterocyclyl each of which has 1 to 4 heteroatoms selected from N and O,

where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl maybe optionally substituted, and the substituents are one or more selectedfrom the group consisting of hydroxy, halogen, nitrile, amino,C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-alkyl,halogeno-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkoxy and oxo.

In the compounds of formula (1) of the present invention, thesubstituent Y more preferably represents a direct bond, —O—, —(CH₂)O—,—(CH₂)— or —(CH₂)SO₂—.

The substituent R1 more preferably represents —(CH₂)_(p)-A-R6 or—(CR4R5)_(q)—R6, wherein p denotes a number of 0 to 2, q denotes anumber of 1 to 3, R4 and R5 independently of one another representhydrogen or C₁-C₅-alkyl, A represents 6˜12 membered aryl or optionallyoxo-containing C₃-C₆-cycloalkyl or represents 5˜6 membered heterocyclylwhich has 1 to 2 hetero atoms selected from O, S, and N, and R6represents hydrogen, halogen, nitro, C₁-C₆-alkylcarbonyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxycarbonyl or carboxy. Most preferably,R1 is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, difluorocyclohexyl, tetrahydrofuran, tetrahydropyran,(tetrahydropyran-4-yl)methyl, tetrahydrothiopyran, 4-oxo-cyclohexyl,(1-methane sulfonyl)pyrrolidine, (1-acetyl)piperidine, 4-nitrophenyl andmethylpropiolate.

The substituent R2 more preferably represents hydrogen, halogen,C₁-C₃-alkyl or trifluoromethyl, represents 5˜6 membered heteroaryl orheterocyclyl each of which has 1 to 3 hetero atoms selected from N andO, or represents optionally methanesulfonyl-substituted 6˜10 memberedaryl. Most preferably, R2 is selected from the group consisting ofhydrogen, fluoro, chloro, bromo, methyl, ethyl, propyl, phenyl,methanesulfonylphenyl, pyridine, morpholine, 1,2-imidazole,1,3-imidazole, pyrrolidine and pyrrole.

In the group R7-X—B—X′— of the substituent R3, the substituent B morepreferably represents a direct bond, represents pyrazole, imidazole oroxadiazole each of which is optionally substituted by C₁-C₆-alkyl, orrepresents 5˜9 membered heterocyclyl which optionally contains oxo, isoptionally fused, and has 1 to 4 hetero atoms selected from N, S and O.Most preferably, B represents a direct bond, or may be a structureselected from the following formulae (i) to (xi)

in which R7 is as defined above.

The substituent X′ more preferably represents a direct bond, or isselected from the group consisting of —CO—, —NR4CO—, —SO₂— and —O—.

The substituent X more preferably represents a direct bond, or isselected from the group consisting of —C(O)NR4-, —NR4-, —OC(O)—,—NR4C(O)—, —(CH₂)C(O)—, —S(O)₂— and —C(O)—. Most preferably, Xrepresents a direct bond, or is selected from the group consisting of—C(O)NH—, —C(O)N(Me)-, —NH—, —N(Me)-, —OC(O)—, —N(Me)C(O)—, —(CH₂)C(O)—,—S(O)₂— and —C(O)—.

The substituent R7 more preferably represents hydrogen, hydroxy,C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl or C₄-C₆-cycloalkyl, representsoptionally halogen-substituted 6˜10 membered aryl, or represents 5˜6membered heteroaryl or heterocyclyl each of which has 1 to 4 heteroatoms selected from N and O. Most preferably, R7 is selected from thegroup consisting of hydrogen, hydroxy, methyl, trifluoromethyl, ethyl,t-butyl, cyclohexyl, pyrrolidine, phenyl, 2-fluorophenyl, piperidine,pyridine, 1,3-pyrazine, 1,4-pyrazine, furan, trifluoromethyl,1,2,3,4-tetrazole and tetrahydrofuran.

Typical compounds among the compounds of formula (1) are those selectedfrom the following:

-   [(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol;-   {(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   {(R)-2-[7-(tetrahydro-furan-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   {(R)-2-[7-(1-methanesulfonyl-pyrrolidin-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   [(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;-   {(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   [(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;-   {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   {(R)-2-[5-chloro-7-(tetrahydro-thiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   [(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;-   {(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   [(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;

{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;

{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;

-   Cyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine;-   Cyclopentyl-[2-((R)-4-morpholin-4-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine;-   Cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine;-   {(R)-2-[5-morpholin-4-ylmethyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   [(R)-2-[7-cyclopentylamino-5-pyrazol-1-ylmethyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl]-methanol;-   [(R)-2-(7-cyclopentylamino-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;-   {(R)-2-[7-cyclopentylamino-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;-   [(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;-   [7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-5-yl]-methanol;-   [(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methyl ester;-   [(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid ethyl ester;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-ethanol;-   {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid methyl ester;-   {(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;-   [(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   2-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-ethanol;-   {(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   2-{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;-   [(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid ethyl ester;-   2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;-   {(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;-   [(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid ethyl ester;-   2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;-   {(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;-   [(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methyl ester;-   [(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid ethyl ester;

{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester;

-   {(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-propoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;

{(R)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;

-   {(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid methyl ester;-   {(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   {(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid methyl ester;-   {(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methyl ester;-   [(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   {(R)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   {(R)-2-[5-methyl-7-(4-oxo-cyclohexylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   {(R)-2-[7-cyclopentylamino-5-(4-methanesulfonyl-phenoxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methyl ester;-   [(R)-2-(7-cyclopentylamino-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   [(R)-2-(7-cyclopentylamino-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methyl ester;-   [(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methyl ester;-   [(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;-   Cyclopentyl-{5-methanesulfonylmethyl-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   1-(4-{2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)-acetamide;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N,N-dimethyl-acetamide;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(3-dimethylamino-pyrrolidin-1-yl)-ethanone;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone;-   2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-piperidin-1-yl-ethanone;-   2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-N-methyl-acetamide;-   2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-1-morpholin-4-yl-ethanone;-   2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-ethanone;-   2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;-   1-(4-Acetyl-piperazin-1-yl)-2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanone;-   2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide;-   2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone;-   2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-ethyl-acetamide;-   2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide;-   2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone;-   N-methyl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetamide;-   1-Morpholin-4-yl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanone;-   {5-Chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   {5-Chloro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   {5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   (5-Chloro-2-{(R)-4-[2-(4-ethanesulfonyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;-   1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;-   (5-Chloro-2-{(R)-4-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;-   1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperidin-4-ol;-   (4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one;-   (5-Chloro-2-{(R)-4-[2-(3-dimethylamino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;-   {5-Chloro-2-[(R)-4-(2-piperidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   (5-Chloro-2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;-   {5-Chloro-2-[(R)-4-(2-pyrazol-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   (S)-1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidine-2-carboxylic    acid;-   {5-Chloro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic    acid ethyl ester;-   3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylic    acid;-   1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-2-one;-   1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylic    acid;-   1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylic    acid dimethylamide;-   [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamic    acid t-butyl ester;-   (2-{(R)-4-[2-((S)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   N—[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-acetamide;-   {5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;-   1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone;-   1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-tetrazol-1-yl-ethanone;-   1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-3,3,3-trifluoro-propan-1-one;-   [4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-furan-2-yl-methanone;-   (5-Chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   (5-Chloro-2-{(R)-4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   {2-[(R)-4-(2-amino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-cyclopentyl-amine;-   1-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   Cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-amine;-   Cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   Cyclopentyl-(2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-1H-indol-7-yl)-amine;-   4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one;-   1-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;-   Cyclopentyl-{5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   {2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;-   {5-Fluoro-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;-   {5-Fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;-   1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl-piperazin-1-yl)-ethanone;-   (2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)-amine;-   (5-Fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;-   4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one;-   1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone;-   Cyclopentyl-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   Cyclopentyl-{2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   Cyclopentyl-{2-[(R)-4-(2-piperidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   {2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;-   1-(4-{2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;-   2-Hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-ethanone;-   3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid ethyl ester;-   3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propan-1-ol;-   3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propionic    acid;-   3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propan-1-ol;    3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-propionamide;-   3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-one;-   1-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propyl}-piperazin-1-yl)-ethanone;-   {5-Chloro-2-[(R)-4-(3-morpholin-4-yl-propyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;-   3-[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid ethyl ester;-   3-[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid ethyl ester;-   3-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid ethyl ester;-   3-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid ethyl ester;-   3-[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid ethyl ester;-   3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionic    acid;-   [(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethoxy]-acetic    acid ethyl ester;-   [(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethoxy]-acetic    acid;-   Cyclopentyl-{2-[(R)-4-(3-cyclopentyl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   Cyclopentyl-{2-[(R)-4-(3-piperidin-1-yl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   [(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   1-(4-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-7-phenoxy-1H-indole;-   7-Phenoxy-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indole;-   Dimethyl-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-amine;-   [(S)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   {(S)-2-[7-(1-acetyl-piperidin-4-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   ((S)-2-{7-[(tetrahydro-pyran-2-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-acetic    acid;-   ((S)-2-{7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-acetic    acid;-   {(S)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   {(S)-2-[7-(1-acetyl-pyrrolidin-3-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   [(S)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   ((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-acetic    acid;-   {(S)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   {(S)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   [(S)-2-(7-cyclobutylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   {(S)-2-[5-methyl-7-(tetrahydro-furan-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   {(S)-2-[7-(cyclopropylmethyl-amino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   ((S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-acetic    acid;-   {(S)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   [(S)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid methylester;-   [(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic    acid;-   {(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic    acid;-   (2-{(S)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-cyclopentyl-amine;-   (5-Chloro-2-{(S)-4-[2-((R)-3-dimethylamino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;-   1-(4-{2-[(S)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   1-(4-{2-[(S)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   1-(4-{2-[(S)-2-(5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   {5-Methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;-   1-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;-   Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;-   4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazine-1-carboxylic    acid t-butyl ester;-   Cyclopentyl-(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-phenoxy-1H-indol-7-yl)-amine;-   4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one;-   (4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone;-   Cyclopentyl-(5-phenoxy-2-{(S)-4-[2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-amine;-   Cyclopentyl-[2-((S)-4-{2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-ethyl}-4,5-dihydro-thiazol-2-yl)-5-phenoxy-1H-indol-7-yl)-amine;-   1-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;-   {(R)-1-[2-[(S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl]-ethyl]-pyrrolidin-2-yl}-methanol;-   N—((R)-1-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-3-yl)-acetamide;-   (2-{(S)-4-[2-(4-benzyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-phenoxy-1H-indol-7-yl)-cyclopentyl-amine;-   {5-Methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)methyl-amine;-   {2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-5-phenoxy-1H-indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)-amine;-   4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one;-   Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-amine;-   (4,4-Difluoro-cyclohexyl)-{2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-amine;-   (2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-pyrazin-7-yl]-ethyl)-4,5-dihydro-thiazol-2-yl}-5-phenoxy-1H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl)-amine;-   4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one;    and-   4-(2-{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-phenoxy-7-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one.

Other terms and abbreviations in the present specification may beunderstood to have the meaning conventionally used in this field by askilled artisan, unless otherwise defined.

The compounds of formula (1) according to the present invention can alsoform a pharmaceutically acceptable salt. Such a pharmaceuticallyacceptable salt includes non-toxic acid addition salt containingpharmaceutically acceptable anion, for example, a salt with inorganicacids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoricacid, hydrobromic acid, hydriodic acid, etc.; a salt with organic acidssuch as tartaric acid, formic acid, citric acid, acetic acid,trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid,lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; or a saltwith sulfonic acids such as methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, etc. Also, for example,the pharmaceutically acceptable carboxylic acid salt includes a saltwith alkali metals or alkaline earth metals such as lithium, sodium,potassium, calcium, magnesium, etc.; a salt with amino acids such aslysine, arginine, guanidine, etc.; or an organic salt withdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,diethanolamine, choline, triethylamine, etc. The compounds of formula(I) of the present invention may be converted to their salts accordingto any of the conventional methods.

The compounds of formula (1) of the present invention may have anasymmetric carbon center(s) in the structure, and so may exist in theform of R or S isomer, racemate, mixture of diastereomers, or individualdiastereomer, etc. All the isomers are also covered by the presentinvention.

The present invention also provides processes for preparing thecompounds of formula (1). Hereinafter, the processes for preparing thecompounds of formula (1) are illustrated by exemplary reaction schemesfor the purpose of better understanding. However, a skilled artisan inthe field to which the present invention pertains may prepare thecompounds of formula (1) via various routes according to theirstructures, and such processes should be construed to fall under thescope of the present invention. In other words, the compounds of formula(1) may be prepared by optionally combining various synthetic methodswhich are described in the present specification or disclosed in theprior arts. The processes for preparing the compounds of formula (1)cover even such processes, and are not limited to those explained below.

The compounds of formula (1) can be prepared according to the followingReaction Scheme (1) by reducing the nitro group of Compound (2) to givean amine Compound (3), and introducing R1 substituent to the resultingamine group. Alternatively, the compounds of formula (1) can be preparedaccording to the following Reaction Schemes (2) to (7) by modifying R1,R2 and R3 substituents in Compound (4).

Compound (5) can be prepared according to the following Reaction Schemes(8) and (9). Compound (7) can be prepared according to the followingReaction Scheme (10), and Compound (20) can be prepared according to thefollowing Reaction Scheme (11).

in the above Reaction Scheme (1),

a represents Fe, Zn, Pd/C, etc.,

b represents a ketone compound in the form of R1=O, sodiumtriacetoxyborohydride {NaBH(OAc)₃}, sodium cyanoborohydride (NaBH₃CN),etc.,

R1, R2, and R3 are as defined in formula (1), and

R8 represents Y—R2, wherein Y and R2 are as defined in formula (1).

Compound (2) can be prepared according to the following Reaction Schemes(2) to (9).

Compound (3) can be prepared by reducing the Compound (2). The reductionreaction may be carried out using an acid catalyst and metal, or using ametal catalyst in the presence of hydrogen gas.

The acid that can be used in the reduction reaction using an acidcatalyst and metal includes, for example, inorganic acids such ashydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc.,organic carboxylic acids such as acetic acid, trifluoroacetic acid,etc., aminates such as ammonium chloride, preferably hydrochloric acid,acetic acid, ammonium chloride, etc. The acid is typically used in theamount of 0.01˜10 eq., preferably 0.1˜5 eq., with respect to 1 eq. ofthe Compound (2). The metal that can be used includes, for example,iron, zinc, lithium, sodium, tin (usually, tin chloride), etc.,particularly preferably iron, zinc, tin chloride, etc. The metal istypically used in the amount of 1˜20 eq., preferably 1˜10 eq., withrespect to 1 eq. of the Compound (2). The reaction of metal in thepresence of an acid catalyst may be carried out in an inert solvent. Asthe inert solvent, for example, alkyl alcohols such as methanol,ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc., alkylesters such as ethyl acetate, etc., preferably methanol, ethanol,tetrahydrofuran, ethyl acetate, etc. can be mentioned. The reactiontemperature is typically in the range of −10˜200° C., preferably 25˜120°C., and the reaction time is typically in the range of 10 min ˜60 h,preferably 10 min˜12 h.

The metal catalyst that can be used in the reduction reaction using ametal catalyst in the presence of hydrogen gas includes palladium,nickel, platinum, ruthenium, rhodium, etc., particularly preferablypalladium, nickel, etc. The metal catalyst is typically used in theamount of 0.001˜2 eq., preferably 0.01˜1 eq., with respect to 1 eq. ofthe Compound (2). The hydrogen gas pressure is typically in the range of1˜10 atm, preferably 1˜3 atm. The reaction may be carried out in aninert solvent, for example, alkyl alcohols such as methanol, ethanol,etc., ethers such as tetrahydrofuran, diethylether, etc., alkyl acetatessuch as methyl acetate, ethyl acetate, etc., preferably methanol,ethanol, ethyl acetate, etc. The reaction temperature using the metalcatalyst is typically in the range of −10˜200° C., preferably 25˜50° C.,and the reaction time is typically in the range of 10 min˜60 h,preferably 10 min˜12 h.

Compound (4) can be prepared via a reductive alkylation reaction of theCompound (3).

The reductive alkylation on the amine group of the Compound (3) may becarried out with a ketone using a reducing agent, and if necessary,using an acid catalyst. The ketone is typically used in the amount of1˜10 eq., preferably 1˜3 eq., with respect to 1 eq. of the Compound (3).The reducing agent that can be used includes sodium borohydride, sodiumcyanoborohydride, sodium triacetoxyborohydride, etc. The reducing agentis typically used in the amount of 1˜10 eq., preferably 1˜3 eq., withrespect to 1 eq. of the Compound (3). The acid catalyst that can be usedincludes, for example, inorganic acids such as hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid, etc., organic carboxylicacids such as acetic acid, trifluoroacetic acid, etc., aminates such asammonium chloride, particularly preferably hydrochloric acid, aceticacid, etc. The acid is typically used in the amount of 0.1˜10 eq.,preferably 1˜5 eq., with respect to 1 eq. of the Compound (3). Thereaction may be carried out in an inert solvent selected, for example,from ethers such as tetrahydrofuran, diethylether, etc., chloroalkanessuch as dichloromethane, chloroform, dichloroethane, etc., preferablydichloroethane, chloroform, etc. The reaction temperature is typicallyin the range of −10˜100° C., preferably −10˜50° C., and the reactiontime is typically in the range of 10 min˜60 h, preferably 10 min˜12 h.

The Compound (1) or (2) of the present invention can be preparedaccording to the processes that are specifically exemplified in thefollowing Reaction Schemes (2) to (9).

in the above Reaction Scheme (2),

a represents a metal hydroxide (for example, NaOH, LiOH),

b represents a coupling agent (for example, EDC, CDI, BOP—Cl) andCompound (7),

c represents PCl₅ or Tf₂O and Ph₃PO,

d represents a coupling agent (for example, EDC, CDI, BOP—Cl) andCompound (11),

R8 is as defined in the Reaction Scheme (1),

R9 represents C₁-C₆-alkyl,

R10 represents NO₂ or R1-X, wherein X and R1 are as defined in formula(1)

R11 represents p-MeOBn or Ph₃C, and

R3′ and R3″ independently of one another represent R7-X—B—, wherein R7,X and B are as defined in formula (1).

Compound (5) can be prepared according to Reaction Schemes (8) and (9).

Compound (6) can be prepared via hydrolysis reaction of the Compound (5)using a base. The base that can be used includes lithium hydroxide,sodium hydroxide, potassium hydroxide, etc. The base is typically usedin the amount of 1˜10 eq., preferably 1˜5 eq., with respect to 1 eq. ofthe Compound (5). The hydrolysis reaction may be carried out in an inertsolvent selected, for example, from water, alkyl alcohols such asmethanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether,etc. The reaction temperature is typically in the range of −10˜200° C.,preferably 25˜120° C., and the reaction time is typically in the rangeof 10 min˜60 h, preferably 10 min˜12 h.

Compound (7) can be prepared according to the following Reaction Schemes(10) and (11).

Compound (8) can be prepared via a coupling reaction of the carboxylicacid of Compound (6) with the amine group of the Compound (7). The knowncoupling agent that can be used in the coupling reaction includes, butnot limited to, carboimides such as dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),1,1′-dicarbonyldiimidazole (CDI), etc. mixed with1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT),or bis-(2-oxo-3-oxazolidinyl)-phosphinic acid chloride (BOP-Cl),diphenylphosphorylazide (DPPA),N-[dimethylamino-1H-1,2,3-triazole[4,5-b]-pyridin-1-ylmethylene]-N-methylmethaneaminium(HATU), etc. The coupling agent is typically used in the amount of 1˜10eq., preferably 1˜3 eq., with respect to 1 eq. of the Compound (6). Theamount of HOBT or HOAT used is typically in the range of 1-10 eq.,preferably 1˜3 eq., with respect to 1 eq. of the Compound (6). When anamine hydrochloride is used in the coupling reaction, the acid should beremoved by using a base. The base that can be used includes organicbases such as triethylamine, diisopropylethylamine The base is typicallyused in the amount of 1˜10 eq., preferably 1˜3 eq., with respect to 1eq. of the Compound (7). The coupling reaction may be carried out in aninert solvent selected from tetrahydrofuran, diethylether,N,N-dimethylformamide, etc. The reaction temperature is typically in therange of −10˜200° C., preferably 25˜120° C., and the reaction time istypically in the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (9) can be prepared by cyclizing the Compound (8) as describedin Journal of Organic Chemistry, 68(24), 2003, 9506˜9509, Tetrahedron,55(34), 1999, 10271˜40282, etc.

When R11 is p-methoxybenzyl (p-MeOBn) group, the cyclization reaction iscarried out in dichloromethane solvent using phosphorus pentachloride(PCl₅). PCl₅ is typically used in the amount of 1˜10 eq., preferably 1˜3eq., with respect to 1 eq. of the Compound (8). The reaction temperatureis typically in the range of −10˜50° C., preferably 0˜25° C., and thereaction time is typically in the range of 10 min˜60 h, preferably 10min˜12 h.

When R11 is triphenylmethyl (Ph₃C) group, the cyclization reaction iscarried out in dichloromethane solvent usingtrifluoromethanesulfonic-anhydride (Tf₂O) and triphenylphosphineoxide(Ph₃PO), which are typically used in the amount of 1˜10 eq., preferably1˜3 eq., with respect to 1 eq. of the Compound (8). The reactiontemperature is typically in the range of −10˜50° C., preferably 0˜25°C., and the reaction time is typically in the range of 10 min˜60 h,preferably 10 min˜12 h.

Compound (11) is an amine compound that is commercially available.

Compound (12) can be prepared via a coupling reaction of the carboxylicacid of the Compound (10) with the Compound (11) according to thepreparing process of the Compound (8).

in the above Reaction Scheme (3),

a represents a reducing agent (for example, NaBH₄, LiAlH₄),

b represents I₂ or MsCl, etc.,

c represents a base and the Compound (11),

d represents a base and Compound (15),

R8 is as defined in Reaction Scheme (1),

R9 represents C₁-C₆-alkyl,

R10 represents NO₂ or R 1-X, wherein X and R1 are as defined in formula(1),

R12 represents C₁-C₆-alkoxy, cyano or 5-6 membered heteroaryl,

R′ and R″ are as defined in the Reaction Scheme (2), and

W represents a leaving group, for example, halides such as chloride,bromide, iodide, etc., or sulfonates such as methane sulfonate,p-toluene sulfonate, etc.

Compound (13) can be prepared by converting the ester group of Compound(9) to an alcohol group. The reducing agent that can be used to reducethe ester group to the alcohol group includes, for example, sodiumborohydride, lithium borohydride, borane, lithium aluminum hydride,diisobutyl aluminum hydride (DIBAL-H), etc. The reducing agent istypically used in the amount of 1˜10 eq., preferably 1˜3 eq., withrespect to 1 eq. of the Compound (9). The reaction may be carried out inan inert solvent selected, for example, from alcohols such as methanol,ethanol, etc., ethers such as tetrahydrofuran, diethylether, etc.,preferably tetrahydrofuran, diethylether, etc. The reaction temperatureis typically in the range of −78˜100° C., preferably −78˜50° C., and thereaction time is typically in the range of 10 min˜60 h, preferably 10min˜12 h.

Compound (14) can be prepared by converting the alcohol group of theCompound (13) to a leaving group W. The leaving group W can beintroduced via halogenation or sulfonation reaction. The halogenationreaction may be carried out using a halogenating agent selected fromiodine, bromine, N-iodosuccimide (NIS), N-bromosuccimide (NBS), carbontetrachloride (CCl₄), carbon tetrabromide (CBr₄), etc. in the presenceof a base such as imidazole, dimethylaminopyridine (DMAP), etc. andphosphines such as triphenylphosphine (Ph₃P), tributylphosphine (Bu₃P),etc. Each of the halogenating agent, base and phosphine is typicallyused in the amount of 1˜10 eq., preferably 1˜3 eq., with respect to 1eq. of the Compound (13). This reaction may be carried out in an inertsolvent selected, for example, from ethers such as tetrahydrofuran,diethylether, etc. and dichloromethane, chloroform, etc. The reactiontemperature is typically in the range of −10˜200° C., preferably 0˜50°C., and the reaction time is typically in the range of 10 min˜60 h,preferably 10 min˜12 h.

The sulfonation reaction may be carried out using a sulfonating agentselected from methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.in the presence of an organic base such as pyridine, triethylamine, etc.Each of the sulfonating agent and base is typically used in the amountof 1˜10 eq., preferably 1˜5 eq., with respect to 1 eq. of the Compound(13). This reaction may be carried out in an inert solvent selected, forexample, from ethers such as tetrahydrofuran, diethylether, etc.,chloroalkanes such as dichloromethane, dichloroethane, chloroform, etc.,preferably dichloromethane, dichloroethane, etc. The reactiontemperature is typically in the range of −10˜200° C., preferably 0˜50°C., and the reaction time is typically in the range of 10 min˜60 h,preferably 10 min˜12 h.

Compound (16) can be prepared by a coupling reaction of the Compound(11) with the Compound (14) using a base. As the base, for example,inorganic bases such as sodium carbonate, potassium carbonate, cesiumcarbonate, etc., organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), etc. can be mentioned.The base is typically used in the amount of 1˜10 eq., preferably 1 ˜5eq., with respect to 1 eq. of the Compound (14). This reaction may becarried out in an inert solvent selected, for example, from ethers suchas tetrahydrofuran, diethylether, etc., alkyl nitriles such asacetonitrile, propionitrile, etc., amides such as N,N-dimethylformamide,etc., preferably tetrahydrofuran, acetonitrile, N,N-dimethylformamide,etc. The reaction temperature is typically in the range of −10˜200° C.,preferably 25˜120° C., and the reaction time is typically in the rangeof 10 min ˜60 h, preferably 10 min˜12 h.

Compound (17) can be prepared via a coupling reaction of the Compound(14) with the Compound (15) according to the preparing process of theCompound (16).

in the above Reaction Scheme (4),

a represents a coupling agent (for example, EDC, CDI, BOP—Cl) andCompound (18),

R8 is as defined in the Reaction Scheme (1),

R10 represents NO₂ or R 1-X, wherein X and R1 are as defined in formula(1), and

R13 represents C₃-C₆-cycloalkyl or piperidinyl.

Compound (18) can be prepared according to a method known inHeterocycles, 60(10), 2087, 2003 or Bioorganic & Medicinal ChemistryLetters, 11(24), 3164, 2001.

Compound (19) can be prepared via a coupling reaction of the Compound(10) with the Compound (18). As the coupling agent,dicyclohexylcarbodiimide (DCC),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC),1,1′-dicarbonyldiimidazole (CDI), etc. can be used, but not limitedthereto. The coupling agent is typically used in the amount of 1˜10 eq.,preferably 1˜3 eq., with respect to 1 eq. of the Compound (10). Thisreaction may be carried out in an inert solvent selected fromtetrahydrofuran, diethylether, N,N-dimethylformamide, etc. The reactiontemperature is typically in the range of −10˜200° C., preferably 25˜120°C., and the reaction time is typically in the range of 10 min˜60 h,preferably 10 min˜12 h.

in the above Reaction Scheme (5),

a represents a coupling agent (for example, EDC, CDI, BOP-Cl),

b represents PCl₅ or Tf₂O and Ph₃PO,

c represents a metal hydroxide (for example, NaOH, LiOH),

d represents I₂ or MsCl, etc.,

e represents a base and the Compound (11),

R8 is as defined in the Reaction Scheme (1),

R10 represents NO₂ or R1-X, wherein X and R1 are as defined in formula(1)

R11 represents p-MeOBn or Ph₃C,

R14 represents C₁-C₆-alkyl,

R′ and R″ are as defined in the Reaction Scheme (2), and

W represents a leaving group, for example, halides such as chloride,bromide, iodide, etc., or sulfonates such as methane sulfonate,p-toluene sulfonate, etc.

Compound (20) can be prepared according to the Reaction Scheme (11).

Compound (21) can be prepared using the Compounds (6) and (20) accordingto the preparing process of the Compound (8) in the Reaction Scheme (2).

Compound (22) can be prepared using the Compound (21) according to thepreparing process of the Compound (9) in the Reaction Scheme (2).

Compound (23) can be prepared using the Compound (22) according to thepreparing process of the Compound (6) in the Reaction Scheme (2).

Compound (24) can be prepared using the Compound (23) according to thepreparing process of the Compound (14) in the Reaction Scheme (3).

Compound (25) can be prepared using the Compound (24) according to thepreparing process of the Compound (16) in the Reaction Scheme (3).

in the above Reaction Scheme (6),

a represents di-t-butyloxy-dicarbonyl (Boc₂O), a base (for example,NaOH, K₂CO₃),

b represents a brominating agent (for example, N-bromosuccinimide(NBS)),

c represents sodium acetate (NaOAc),

d represents an acid (for example, hydrochloric acid, trifluoroaceticacid),

e represents a metal hydroxide (for example, NaOH, LiOH),

f represents a coupling agent (for example, EDC, CDI, BOP—Cl) andCompound (33),

g represents PCl₅,

h represents a base and the Compound (33),

R2 is as defined in formula (1),

R9 represents C₁-C₆-alkyl,

R11 represents p-MeOBn, and

R15 represents C₁-C₆-alkoxycarbonyl or C₁-C₆-alkylcarbonyloxy.

Compound (26) can be prepared according to Reaction Scheme (9).

Compound (27) can be prepared by protecting the amine group of theCompound (26) using Boc₂O in the presence of a base, and converting themethyl group to bromomethyl group using a brominating agent, in theorder.

Boc₂O used in the protection reaction of amine group is typically usedin the amount of 1˜10 eq., preferably 1˜3 eq., with respect to 1 eq. ofthe Compound (26). The base is typically used in the amount of 1˜10 eq.,preferably 1˜3 eq., with respect to 1 eq. of the Compound (26). Acatalyst may be used for facilitating the reaction. The catalyst used isdimethylaminopyridine (DMAP), and typically used in the amount of 0.01˜2eq., preferably 0.1˜0.3 eq., with respect to 1 eq. of the Compound (26).This reaction may be carried out in an inert solvent selected fromtetrahydrofuran, diethylether, N,N-dimethylformamide, dichloromethane,etc. The reaction temperature is typically in the range of −10˜200° C.,preferably 25˜120° C., and the reaction time is typically in the rangeof 10 min˜60 h, preferably 10 min˜12 h.

The brominating agent used in the bromomethylation reaction includesN-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin, and istypically used in the amount of 1˜10 eq., preferably 1˜3 eq., withrespect to 1 eq. of the Compound (26). A catalyst may be used forfacilitating the reaction. The catalyst used is2,2′-azidobis(2-methylpropionitrile) (AIBN) or benzoyl peroxide, andtypically used in the amount of 0.001˜2 eq., preferably 0.01˜0.3 eq.,with respect to 1 eq. of the Compound (26). This reaction may be carriedout in an inert solvent selected from benzene, toluene, carbontetrachloride, etc. The reaction temperature is typically in the rangeof −10˜200° C., preferably 25˜120° C., and the reaction time istypically in the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (28) can be prepared by reacting sodium acetate (NaOAc) withthe Compound (27). Sodium acetate is typically used in the amount of1˜10 eq., preferably 1˜5 eq., with respect to 1 eq. of the Compound(27). This reaction may be carried out in an inert solvent, for example,selected from ethers such as tetrahydrofuran, diethylether, etc., alkylnitriles such as acetonitrile, propionitrile, etc., amides such asN,N-dimethylformamide, etc. The reaction temperature is typically in therange of −10 ˜200° C., preferably 25˜120° C., and the reaction time istypically in the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (29) can be prepared by removing the BOC group using an acid,and hydrolysis reaction using a base, in the order. The acid used in theremoval of BOC group is hydrochloric acid, trifluoroacetic acid, etc.The acid is typically used in the amount of 1˜10 eq., preferably 2˜5eq., with respect to 1 eq. of the Compound (28). This reaction may becarried out in an inert solvent, for example, selected from ethers suchas tetrahydrofuran, diethylether, dioxane, etc., alkyl alcohols such asmethanol, ethanol, etc., chloroalkanes such as dichloromethane,chloroform, etc. The reaction temperature is typically in the range of−10˜200° C., preferably 25˜120° C., and the reaction time is typicallyin the range of 10 min˜60 h, preferably 10 min˜12 h.

The base used in the hydrolysis reaction includes lithium hydroxide,sodium hydroxide, potassium hydroxide, etc. The base is typically usedin the amount of 2˜20 eq., preferably 2˜10 eq., with respect to 1 eq. ofthe Compound (28). This hydrolysis reaction may be carried out in aninert solvent, for example, selected from alkyl alcohols such asmethanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether,etc. The reaction temperature is typically in the range of −10˜200° C.,preferably 25˜120° C., and the reaction time is typically in the rangeof 10 min˜60 h, preferably 10 min˜12 h.

Compound (30) can be prepared according to Reaction Schemes (10) and(11).

Compound (31) can be prepared via a coupling reaction of the Compound(29) with the Compound (30) according to the preparing process of theCompound (8) in the Reaction Scheme (2).

Compound (32) can be prepared by reacting PCl₅ with the Compound (31).In this reaction of using PCl₅, cyclization and chlorination of thealcohol group occur simultaneously. PCl₅ is typically used in the amountof 1˜10 eq., preferably 1˜3 eq., with respect to 1 eq. of the Compound(31). This reaction may be carried out in a solvent selected fromdichloromethane, chloroform, etc. The reaction temperature is typicallyin the range of −10˜200° C., preferably 0˜50° C., and the reaction timeis typically in the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (33) is commercially available.

Compound (34) can be prepared via a coupling reaction of the Compound(32) with the Compound (33) according to the preparing process of theCompound (16).

in the above Reaction Scheme (7),

a represents an acylating agent [for example, R11-CO—Cl, (R11-CO)₂O],

b represents PCl₅,

c represents a metal hydroxide (for example, NaOH, LiOH),

R11 represents p-MeOBn,

R14 represents C₁-C₆-alkyl, and

R15 represents C₁-C₆-alkoxycarbonyl or C₁-C₆-alkylcarbonyloxy.

Compound (35) can be prepared by protecting the alcohol group of theCompound (31) with an acyl group, and cyclizing using PCl₅. Theprotection reaction of the alcohol group is carried out using a base andan acylating agent. The base used includes organic bases such astriethylamine, diisopropylethylamine, pyridine, etc. The base istypically used in the amount of 1˜10 eq., preferably 1˜5 eq., withrespect to 1 eq. of the Compound (31). The acylating agent used is acompound in the form of R14-CO—Cl or (R14-CO)₂O(R14=C₁˜C₆-alkyl). Theacylating agent is typically used in the amount of 1˜10 eq., preferably1˜3 eq., with respect to 1 eq. of the Compound (31). This reaction maybe carried out in a solvent selected from dichloromethane, chloroform,dichloroethane, etc. The reaction temperature is typically in the rangeof −10˜200° C., preferably 0˜50° C., and the reaction time is typicallyin the range of 10 min˜60 h, preferably 10 min˜12 h.

The cyclization reaction uses PCl₅. PCl₅ is typically used in the amountof 1˜10 eq., preferably 2˜5 eq., with respect to 1 eq. of the Compound(31). This reaction may be carried out in a solvent selected fromdichloromethane, chloroform, etc. The reaction temperature is typicallyin the range of −10˜200° C., preferably 0˜50° C., and the reaction timeis typically in the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (36) can be prepared via a deprotection reaction of thehydroxyl group of the Compound (35) using a base. The base used in thedeprotection reaction includes lithium hydroxide, sodium hydroxide,potassium hydroxide, etc. The base is typically used in the amount of1˜10 eq., preferably 1˜5 eq., with respect to 1 eq. of the Compound(35). This reaction may be carried out in an inert solvent, for example,selected from water, alkyl alcohols such as methanol, ethanol, etc.,ethers such as tetrahydrofuran, diethylether, etc. The reactiontemperature is typically in the range of −10˜200° C., preferably 25˜120°C., and the reaction time is typically in the range of 10 min˜60 h,preferably 10 min˜12 h.

in the above Reaction Scheme (8),

a represents sodium nitrite (NaNO₂); tin chloride (SnCl₂),

b represents a ketone compound (39), a base (for example, NaOAc),

c represents an acid (for example, polyphosphoric acid PPA),

d represents NaNO₂,

e represents Compound (42), a base (for example, NaOH),

R8 is as defined in the Reaction Scheme (1), and

R9 and R10 are as defined in the Reaction Scheme (2).

Compound (37) is commercially available, or can be prepared by a methodknown in Heterocycles, 68(11), 2285˜99, 2006, or Bioorganic & MedicinalChemistry Letters, 14(19), 4903˜4906, 2004.

Compound (38) is commercially available, or can be prepared byconverting the amine group of the Compound (37) to hydrazine groupaccording to a method known in Journal of the American Chemical Society,198(48), 15374˜75, 2006.

Alternatively, the hydrazine Compound (38) can be prepared by reactingthe amine group of the Compound (37) with NaNO₂ in the presence ofhydrochloric acid to give a diazonium salt (41), which is not separatedand reduced by using SnCl₂. NaNO₂ is typically used in the amount of1˜10 eq., preferably 2˜5 eq., with respect to 1 eq. of the Compound(37). SnCl₂ is typically used in the amount of 1˜10 eq., preferably 2˜5eq., with respect to 1 eq. of the Compound (37). This reaction iscarried out in 1˜12N, preferably 4˜8N, aqueous hydrochloric acidsolution. The reaction temperature is in the range of −10˜50° C., andthe reaction time is typically in the range of 10 min˜60 h, preferably10 min˜6 h.

Compound (39) is commercially available.

Hydrazone Compound (40) can be prepared via a coupling reaction of theCompound (38) with the ketone Compound (39). A base is not used when theCompound (38) is in neutral form, but should be used when the Compound(38) is in the form of an acid salt to make the neutral form. As thebase, for example, metal hydroxides such as sodium hydroxide, lithiumhydroxide, etc., metal carbonates such as sodium bicarbonate, potassiumcarbonate, etc., metal acetates such as sodium acetate, etc., organicbases such as triethylamine, pyridine, etc., preferably sodium acetate,sodium bicarbonate, etc. can be used. The base is typically used in theamount of 1˜5 eq., preferably 1˜2 eq., with respect to 1 eq. of theCompound (38). This reaction may be carried out in an inert solventselected from tetrahydrofuran, methanol, ethanol, etc. The reactiontemperature is in the range of −10˜100° C., and the reaction time istypically in the range of 10 min˜60 h, preferably 10 min˜12 h.

The Compound (40) can also be prepared by reacting the diazonium salt(41) with the Compound (42) in the presence of a base according toJapp-Klingemann rearrangement method described in Organic ProcessResearch & Development, 2, 1988, 214˜220. Hydrochloric acid is used inthe preparation of the diazonium salt (41) typically in the amount of1˜10 eq., preferably 2˜4 eq., with respect to 1 eq. of the Compound(37). The base used in the reaction of the Compounds (41) and (42) issodium hydroxide, which is typically used in the amount of 1˜20 eq.,preferably 1˜10 eq., with respect to 1 eq. of the Compound (42). 80%aqueous ethanol solution is used as the solvent, and the reactiontemperature is in the range of −10˜50° C. The reaction time is typicallyin the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (5) can be prepared using an acid catalyst and the Compound(40). The acid used in the synthesis is polyphosphoric acid,hydrochloric acid, p-toluenesulfonic acid, sulfuric acid, acetic acid,etc., preferably polyphosphoric acid. Polyphosphoric acid can be usedalone, or as a mixture with aromatic hydrocarbons such as benzene,toluene, etc. The reaction temperature is in the range of 25˜150° C.,and the reaction time is typically in the range of 5 min˜60 h,preferably 5 min˜12 h.

in the above Reaction Scheme (9),

a represents a sodium alkoxide (for example, sodium methoxide),

b represents heat,

R1 is as defined in formula (1),

R8 is as defined in the Reaction Scheme (1), and

R9 represents C₁-C₆-alkyl.

Compound (43) is commercially available.

Compound (44) can be prepared by a method known in Journal of MedicinalChemistry, 31(11), 2145, 1988.

Compound (45) is commercially available, or can be prepared by a methodknown in WO 2007040289, WO200601079 or Organic Letters 9(3), 397˜400,2007.

Alternatively, the Compound (45) can be prepared via a coupling reactionof the Compound (43) with the Compound (44) in the presence of a base.The base used is sodium methoxide, sodium ethoxide, etc. The base istypically used in the amount of 1 ˜10 eq., preferably 1˜3 eq., withrespect to 1 eq. of the Compound (43). This reaction may be carried outin an inert solvent, for example, selected from alkyl alcohols such asmethanol, ethanol, etc., ethers such as tetrahydrofuran, diethylether,etc. The reaction temperature is typically in the range of −10˜200° C.,preferably −10˜25° C., and the reaction time is typically in the rangeof 10 min˜60 h, preferably 10 min˜12 h.

Compound (46) can be prepared by cyclizing the Compound (45). Thecyclization reaction may be carried out by dissolving the Compound (45)in an inert solvent, and heating the solution. The inert solvent thatcan be used includes tetrahydrofuran, benzene, toluene, etc. Thereaction temperature is typically in the range of 25˜200° C., preferably50˜120° C., and the reaction time is typically in the range of 10 min˜60h, preferably 10 min˜12 h.

in the above Reaction Scheme (10),

a represents p-methoxybenzylchloride (PMBCl) or triphenylmethyl-chloride(TrCl), a base (for example, NaOH),

b represents di-t-butyloxy-dicarbonyl (Boc₂O), a base (for example,NaOH, K₂CO₃),

c represents an alkylchloroformate (for example, EtOCOCl), a base (forexample, N-methylmorpholine),

d represents diazomethane (CH₂N₂), a base (for example, KOH),

e represents a silver ion (for example, silver benzoate),

f represents an acid,

g represents MsCl, Et₃N,

h represents p-methoxybenzylthiol (PMBSH), NaH,

R9 represents C₁-C₆-alkyl, and

R11 represents p-MeOBn or Ph₃C.

Compound (47) can be prepared by protecting the thiol group of cysteineusing p-methoxybenzyl chloride (PMBCl) or triphenylmethyl chloride(TrCl) in the presence of a base.

PMBCl or TrCl used in the protection reaction of the thiol group istypically used in the amount of 1˜5 eq., preferably 1˜2 eq., withrespect to 1 eq. of cysteine. The base used is sodium hydroxide,potassium carbonate, etc., and is typically used in the amount of 1˜5eq, preferably 1˜2 eq., with respect to 1 eq. of cysteine. This reactionmay be carried out in an inert solvent selected from tetrahydrofuran,methanol, ethanol, water, etc. The reaction temperature is typically inthe range of −10˜200° C., preferably 0˜50° C., and the reaction time istypically in the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (48) can be prepared by protecting the amine group of theCompound (47) using BOC group.

Boc₂O used in the protection reaction of the amine group is typicallyused in the amount of 1˜5 eq., preferably 1˜2 eq., with respect to 1 eq.of cysteine. The base used is selected, for example, from hydroxidessuch as sodium hydroxide, lithium hydroxide, etc., carbonates such assodium carbonate, sodium bicarbonate, potassium carbonate, cesiumcarbonate, etc., organic bases such as diisopropylethylamine,triethylamine, etc., preferably potassium carbonate, triethylamine, etc.This reaction may be carried out in an inert solvent selected fromtetrahydrofuran, methanol, ethanol, water, etc. The reaction temperatureis typically in the range of −10˜200° C., preferably 0˜50° C., and thereaction time is typically in the range of 10 min˜60 h, preferably 10min˜12 h.

Compound (49) can be prepared by a method known in Helvetica ChimicaActa, 87, 2004, 3131˜3159.

1 Eq. of the Compound (48) is reacted with 1˜2 eq. of ethylchloroformate(EtOCOCl) or isobutylchloroformate (^(i)BuOCOCl) in tetrahydrofuransolvent maintained at room temperature in the presence of 1˜2 eq. of abase {for example, N-methylmorpholine (NMM), triethylamine, etc.} togive an anhydride compound. The resulting anhydride compound is reactedwith 1˜5 eq. of diazomethane and 1˜5 eq. of aqueous potassium hydroxidesolution in diethylether solvent maintained at 0° C., and then reactedwith 0.1˜2 eq. of an Ag ion (for example, silver trifluoroacetate(CF₃CO₂Ag), silver benzoate, etc.) and 1˜10 eq. of an alkyl alcohol (forexample, methanol, ethanol, etc.) under the dark condition at roomtemperature to give an alkyl ester.

The reaction for removing the BOC group can be made using an acid. Theacid used includes hydrochloric acid, trifluoroacetic acid, etc. Theacid is typically used in the amount of 1˜10 eq., preferably 2˜5 eq.,with respect to 1 eq. of the Compound (48). This reaction may be carriedout in an inert solvent, for example, selected from ethers such astetrahydrofuran, diethylether, dioxane, etc., alkyl alcohols such asmethanol, ethanol, etc., chloroalkanes such as dichloromethane,chloroform, etc. The reaction temperature is typically in the range of−10˜200° C., preferably 25˜120° C., and the reaction time is typicallyin the range of 10 min˜60 h, preferably 10 min˜12 h.

Compound (50) can be prepared from glutamic acid or aspartic acid by amethod known in Synlett, 15, 2005, 2397˜2399, Journal of OrganicChemistry, 66(5), 2001, 1919˜1923, etc.

Compound (51) can be prepared by sulfonating the Compound (50). Thesulfonation reaction may be carried out using methanesulfonyl chloridein the presence of an organic base such as pyridine, triethylamine, etc.The sulfonylating agent and base each are used in the amount of 1˜10eq., preferably 1˜5 eq., with respect to 1 eq. of the Compound (50).This reaction may be carried out in an inert solvent selected fromdichloromethane, dichloroethane, etc. The reaction temperature istypically in the range of −10˜200° C., preferably 0˜50° C., and thereaction time is typically in the range of 10 min˜60 h, preferably 10min˜12 h.

The Compound (7) can be prepared by reacting p-methoxybenzylthiol(PMBSH) with the Compound (51) in the presence of a base, and removingthe BOC group using an acid. The base used is sodium hydride, potassiumcarbonate, cesium carbonate, etc., preferably sodium hydride. The baseis typically used in the amount of 1˜10 eq., preferably 2˜5 eq., withrespect to 1 eq. of the Compound (51). p-Methoxybenzylthiol (PMBSH) istypically used in the amount of 1˜10 eq., preferably 2 ˜5 eq., withrespect to 1 eq. of the Compound (51). This reaction may be carried outin an inert solvent selected from tetrahydrofuran, dimethylformamide,N-methylpyrrolidinone, etc. The reaction temperature is typically in therange of −10˜200° C., preferably 25˜100° C., and the reaction time istypically in the range of 10 min ˜60 h, preferably 10 min˜12 h.

The reaction for removing BOC group may be carried out in the samemanner as the removal of BOC group explained in the preparing process ofthe Compound (49).

in the above Reaction Scheme (11),

a represents an alkyl alcohol (for example, methanol, ethanol), acetylchloride or thionyl chloride,

b represents di-t-butyloxy-dicarbonyl (Boc₂O), a base (for example,NaOH, K₂CO₃),

c represents a reducing agent (for example, NaBH₄),

d represents an alkylcarbonyl chloride (for example, t-butylcarbonylchloride (^(t)BuCOCl)), a base (for example, Et₃N),

e represents an acid,

R9 represents C₁-C₆-alkyl,

R11 represents p-MeOBn or Ph₃C, and

R14 represents C₁-C₆-alkyl.

Compound (52) can be prepared by esterifying the carboxylic group of theCompound (47), and protecting the amine group with BOC group. Theesterification reaction may be carried out using acetyl chloride orthionyl chloride in an alkyl alcohol solvent. Acetyl chloride or thionylchloride is used in the amount of 1˜10 eq., preferably 1˜5 eq., withrespect to 1 eq. of the Compound (47). The reaction temperature istypically in the range of 25˜200° C., preferably 25˜100° C., and thereaction time is typically in the range of 10 min˜60 h, preferably 10min˜12 h.

The protection reaction of the amine group may be carried out in thesame manner as the preparing process of the Compound (48).

The Compound (20) can be prepared from the starting Compound (52) viareduction of the ester group, protection of the alcohol group, andremoval of BOC, in the order. The reduction reaction of the ester groupmay be carried out by reacting with an alkylchloroformate (for example,ethylchloroformate, isobutylchloroformate) in tetrahydrofuran solvent ofroom temperature in the presence of 1˜5 eq. of a base (for example,triethylamine, diisopropylethylamine, N-methylmorpholine, etc.) to givean anhydride, which is then reacted with 1˜5 eq. of lithium borohydrideor sodium borohydride in aqueous tetrahydrofuran solution of 0˜25° C.for 10 min˜12 h.

The protection reaction of the alcohol group may be carried out byreacting with an alkylcarbonylchloride, for example, t-BuCOCl, indichloromethane solvent of 0˜25° C. in the presence of 1˜5 eq. of a baseselected from triethylamine, pyridine, etc. for 10 min˜12 h.

The reaction for removing BOC group may be carried out by dissolving thereactant in an inert solvent selected from tetrahydrofuran, dioxane,ethyl acetate, dichloromethane, etc. and reacting with 1˜10 eq. ofhydrochloric acid or trifluoroacetic acid at 0˜50° C. for 10 min˜12 h.

The compounds whose preparation methods are not specifically explainedin the present specification are known per se, or can be prepared from aknown compound according to a known process or a similar processthereto.

The compounds of formula (1) obtained by the above processes may beseparated or purified from the reaction product by various methods suchas recrystallization, ionophoresis, silica gel column chromatography,ion exchange chromatography, etc.

As explained above, the compounds according to the present invention,starting materials, intermediates, etc. for the preparation thereof maybe obtained by various processes, and such processes for preparing thecompounds of formula (1) should be construed to fall under the scope ofthe present invention.

EFFECT

The present invention further provides a pharmaceutical composition forthe activation of glucokinase, which comprises the compounds of formula(1), pharmaceutically acceptable salts or isomers thereof as an activeingredient together with pharmaceutically acceptable carriers.

Diseases which are caused by the deactivation of glucokinase, and can beprevented or treated by the pharmaceutical composition of the presentinvention include, but not limited to, diabetes, complications ofdiabetes, obesity, etc. The pharmaceutical composition of the presentinvention can be used for the prevention or treatment of type 1 diabetesor type 2 diabetes, and is particularly preferable for type 2 diabetes.The complications of diabetes that can be prevented or treated by thepharmaceutical composition of the present invention include, but notlimited to, hyperlipidemia, hypertension, retinosis, renal failure, etc.

The present invention further provides a hypoglycemic composition whichcomprises the compounds of formula (1), pharmaceutically acceptablesalts or isomers thereof as an active ingredient together withpharmaceutically acceptable carriers.

The present invention further provides a process for preparing apharmaceutical composition for the activation of glucokinase, morespecifically, for the prevention or treatment of diabetes, complicationsof diabetes, or obesity, which comprises the step of mixing thecompounds of formula (1), pharmaceutically acceptable salts or isomersthereof as an active ingredient together with pharmaceuticallyacceptable carriers.

The above-mentioned “pharmaceutical composition” or “hypoglycemiccomposition” may comprise pharmaceutically acceptable carriers,diluents, excipients, or their combinations, if needed, together withthe compounds of the present invention. Pharmaceutical compositionfacilitates the administration of the compound into a living organism.There exist a number of techniques to administer the compound, and theyinclude, but not limited to, oral, injectable, aerosol, parenteral andtopical administration.

As used herein, “carrier” means a substance which facilitates theincorporation of the compound into the cells or tissues. For example,dimethylsulfoxide (DMSO) is a typical carrier which is used tofacilitate the introduction of various organic compounds into the cellsor tissues of living organisms.

As used herein, “diluent” is defined as a substance that is diluted inwater which dissolves the compound, as well as stabilizes thebiologically active form of the subject compound. The salts dissolved inbuffer solution are utilized as diluents in the art. Typically usedbuffer solution is phosphate buffered saline which mimics the salt formof human solution. Buffer diluents rarely alter the biologicalactivities of the compound, as the buffer salts can control the pH ofsolution at a low concentration.

As used herein, “pharmaceutically acceptable” means the property thatdoes not impair the biological activities and physical properties of thecompound.

The compounds of the present invention can be formulated as variouspharmaceutical dosage forms according to the purpose. In preparing thepharmaceutical composition of the present invention, the activeingredient, specifically, the compounds of formula (1), pharmaceuticallyacceptable salts or isomers thereof are mixed together with variouspharmaceutically acceptable carriers which can be selected according tothe formulation to be prepared. For example, the pharmaceuticalcomposition of the present invention can be formulated as injectablepreparation, oral preparation, etc., according to the purpose.

The compounds of the present invention can be formulated by the methodsknown in the art, which utilize pharmaceutical carriers and excipientsknown in the art, and be incorporated into the containers of unit doseform or multi-dose form. The form of the preparation can be solutions,suspensions or emulsions in oily or aqueous media, and may containtypical dispersing agents, suspending agents or stabilizers. Further,for example, it can be a form of dry powder which is intended to bereconstructed by dissolving in sterile, pyrogen-free water prior to use.The compounds of the present invention also can be formulated intosuppository forms utilizing typical suppository bases such as cocoabutter or other glycerides. As solid dosage forms for oraladministration, capsules, tablets, pills, powder and granule can beprepared, and capsules and tablets are especially useful. Preferably,tablets and pills are prepared as enteric coated forms. Solid dosageforms can be prepared by mixing the compounds of the present inventiontogether with carriers, for example, one or more inert diluents such assucrose, lactose, starch, etc., lubricants such as magnesium stearate,disintegrant, binder, etc.

If needed, the compounds of the present invention or the pharmaceuticalcompositions containing the same can also be administered in combinationwith other active agents, for example, other agents for treatingdiabetes.

The dosage of the compounds of formula (1) depends on the prescriptionof a physician, taking into account such factors as body weight or ageof a patient, specific nature of the disease, and severity of thedisease, etc. However, dosage needed for the treatment of an adult istypically from about 1 to 500 mg per day, depending on the intensity andfrequency of the administration. When administered to an adult viaintramuscular or intravenous routes, total dosage typically from about 5to 300 mg per day will be sufficient when separately administered in asingle dosage, but for some patients a higher daily dosage may bedesirable.

The present invention further provides a method for the prevention ortreatment of diseases which are caused by the deactivation ofglucokinase, using effective amount of the compounds of formula (1),pharmaceutically acceptable salts or isomers thereof as an activeingredient.

The present invention further provides a process for preparing apharmaceutical composition for the prevention or treatment of diseaseswhich are caused by the deactivation of glucokinase, which comprises thestep of mixing the compounds of formula (1), pharmaceutically acceptablesalts or isomers thereof as an active ingredient together withpharmaceutically acceptable carriers.

As used herein, “treatment” means the interrupting or delaying theprogress of the disease when applied to the subject showing the onset ofdisease symptoms, and “prevention” means the interrupting or delayingthe sign of the onset of disease when applied to the subject that doesnot show, but is at risk of, the onset of disease symptoms.

The present invention will be more specifically explained by thefollowing preparations and examples. However, it should be understoodthat they are intended to illustrate the present invention but not inany manner to limit the scope of the present invention. In the followingpreparations and examples, M means molar concentration, and N meansnormal concentration.

BEST MODE FOR CARRYING OUT THE INVENTION Preparation 1: Synthesis of2-[(4-fluoro-2-nitro-phenyl)-hydrazono]-propionic acid ethyl ester

4-Fluoro-2-nitroaniline (10 g, 64 mmol) was dissolved in 6N hydrochloricacid (64 ml, 0.27 mol), sodium nitrate (4.4 g, 64 mmol) dissolved inwater (50 ml) was slowly added in drops thereto at 0° C., and themixture was stirred for 30 min at 0° C.˜room temperature.Simultaneously, ethyl 2-methylacetoacetate (9.2 ml, 64 mmol) and sodiumhydroxide (19 g, 0.34 mol) were dissolved in 80% aqueous ethanolsolution (95 ml), and stirred for 10 min at 0° C. The two solutions thusprepared were mixed, and stirred for 8 h at 0° C.˜room temperature.Water was added to the reaction solution, and the insoluble solid wascollected. The solid was washed with water, and dried to give the titlecompound (7.9 g, Yield 46%).

¹H-NMR (400 HMz, CDCl₃); δ 10.81 (br s, 1H), 8.05 (m, 1H), 7.90 (m, 1H),7.41 (m, 1H), 4.36 (q, 2H), 2.22 (S, 3H), 1.38 (t, 3H)

Preparation 2: Synthesis of 5-fluoro-7-nitro-1H-indole-2-carboxylic acidethyl ester

The compound (8.8 g, 33 mmol) prepared in Preparation 1 was mixed withpolyphosphoric acid (50 ml), and stirred for 7 h at 60° C. Water wasadded to the reaction solution, and the insoluble solid was collected.The solid was washed with water, and dried to give the title compound(3.4 g, Yield 41%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.55 (br s, 1H), 8.16 (m, 1H), 8.10 (m,1H), 7.42 (s, 1H), 4.40 (q, 2H), 1.36 (t, 3H)

Preparation 3: Synthesis of (4-chloro-2-nitro-phenyl)-hydrazinehydrochloride

4-Chloro-2-nitroaniline (40 g, 0.23 mol) was dissolved in 12Nhydrochloric acid (100 ml). At 0° C., sodium nitrate (16 g, 0.23 mol)dissolved in water (50 ml) was slowly added in drops thereto, and themixture was stirred for 30 min at 0° C.˜room temperature. Thetemperature was lowered to 0° C., and tin(II) chloride (132 g, 0.70 mol)dissolved in 12N hydrochloric acid (100 ml) was slowly added in dropsthereto. The mixture was stirred for 3 h at 0° C.˜room temperature. Theresulting yellow solid was filtered, washed with a small quantity of 6NHCl, and dried to give the title compound (30 g, Yield 63%).

¹H-NMR (400 HMz, DMSO-d₆); δ 9.21 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.66(d, J=9.6 Hz, 1H), 7.55 (dd, J=2.4, 9.6 Hz, 1H), 4.74 (br s, 2H)

Preparation 4: Synthesis of2-[(4-chloro-2-nitro-phenyl)-hydrazono]-propionic acid methyl ester

The hydrazine (30 g, 0.14 mol) prepared in Preparation 3 and methylpyruvate (14.4 ml, 0.16 mol) were dissolved in methanol (300 ml), andsodium acetate (14.2 g, 0.17 mol) was added thereto. The mixture wasstirred for 8 h at room temperature. The resulting yellow solid wasfiltered, washed with water and methanol, and dried to give the titlecompound (30 g, Yield 82%).

¹H-NMR (400 HMz, CDCl₃); δ 10.88 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.01(d, J=9.2 Hz, 1H), 7.56 (dd, J=2.4, 9.2 Hz, 1H), 3.90 (s, 3H), 2.23 (s,3H).

Mass Spectrum (ESI, m/z): Calculated for C₁₀H₁₀ClN₃O₄ 271.04. Found271.66

Preparation 5: Synthesis of 5-chloro-7-nitro-1H-indole-2-carboxylic acidmethyl ester

To the compound (13 g, 46 mmol) prepared in Preparation 4 was addedpolyphosphoric acid (100 ml), which was then heated at 100° C. for 4 h.After completion of the reaction, water was added to the reactionsolution, and the insoluble solid was collected. The solid was washedwith water, and dried to give the title compound (6.0 g, Yield 49%).

¹H-NMR (400 HMz, CDCl₃); δ 10.32 (br s, 1H), 8.29 (d, 1H), 8.03 (d,J=2.4 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 4.01 (s, 3H)

Mass Spectrum (ESI, m/z): Calculated 254.01. Found 254.63

Preparation 6: Synthesis of 5-bromo-7-nitro-1H-indole-2-carboxylic acidmethyl ester

4-Bromo-2-nitroaniline (15.6 g, 71.9 mmol) was reacted according to thesame procedures as Preparations 3 to 5 to give the title compound (7.2g, Yield 73%).

¹H-NMR (400 HMz, CDCl₃); δ 10.33 (br s, 1H), 8.41 (s, 1H), 8.18 (s, 1H),7.30 (d, J=4.0 Hz, 1H), 4.01 (s, 3H)

Preparation 7: Synthesis of 5-methyl-7-nitro-1H-indole-2-carboxylic acidmethyl ester

4-Methyl-2-nitroaniline (40 g, 0.26 mol) was reacted according to thesame procedures as Preparations 3 to 5 to give the title compound (20 g,Yield 32%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.25 (br s, 1H), 8.08 (3, 1H), 7.96 (s,1H), 7.32 (s, 1H), 3.87 (s, 3H), 2.44 (s, 3H)

Preparation 8: Synthesis of 7-nitro-1H-indole-2-carboxylic acid methylester

2-Nitroaniline (30 g, 0.21 mol) was reacted according to the sameprocedures as Preparations 3 to 5 to give the title compound (11 g,Yield 23%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.36 (br s, 1H), 8.23 (d, 1H), 8.17 (d,1H), 7.42 (s, 1H), 7.32 (t, 1H), 3.88 (s, 3H)

Preparation 9: Synthesis of 5-methoxy-7-nitro-1H-indole-2-carboxylicacid methyl ester

4-Methoxy-2-nitrophenylamine (30 g, 0.18 mol) was reacted according tothe same procedures as Preparations 3 to 5 to give the title compound(12 g, Yield 27%).

Preparation 10: Synthesis of 4-ethoxy-2-nitro-phenylamine

4-Ethoxyaniline (40 g, 0.29 mol) and triethylamine (61 ml, 0.44 mol)were dissolved in dichloromethane (200 ml). Acetic anhydride (30 ml,0.32 mmol) was added in drops thereto, and the mixture was stirred for 1h at 0° C.˜room temperature. 1N hydrochloric acid solution was addedthereto, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated sodium chloride solution, and dried overanhydrous magnesium sulfate.

The resulting acetamide compound was dissolved in dichloromethane (200ml), and fuming nitric acid (13 ml, 0.29 mol) was added in drops theretoat 0° C. The mixture was stirred for 1 h at 0° C.˜room temperature.Saturated aqueous sodium hydrogen carbonate solution was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated sodium chloride solution, and dried over anhydrous magnesiumsulfate.

The resulting nitrate compound was dissolved in methanol (100 ml) andtetrahydrofuran (100 ml), and 6N sodium hydride was added in dropsthereto. The mixture was stirred for 6 h at room temperature. Aftercompletion of the reaction, the reaction solution was neutralized toabout pH 7 using 6N hydrochloric acid solution, and extracted with ethylacetate. The extract was washed with saturated sodium chloride solution,and dried over anhydrous magnesium sulfate to give the title compound(44 g, Yield 83%).

Preparation 11: Synthesis of 5-ethoxy-7-nitro-1H-indole-2-carboxylicacid methyl ester

4-Ethoxy-2-nitroaniline (40 g, 0.22 mol) prepared in Preparation 10 wasreacted according to the same procedures as Preparations 3 to 5 to givethe title compound (13 g, Yield 22%).

¹H-NMR (400 HMz, DMSO-d₆); δ 10.20 (br s, 1H), 7.86 (s, 1H), 7.51 (s,1H), 7.26 (s, 1H), 4.13 (m, 2H), 3.98 (s, 3H), 1.47 (m, 3H)

Preparation 12: Synthesis of 7-nitro-5-phenoxy-1H-indole-2-carboxylicacid methyl ester

4-Aminophenyl phenyl ether (20 g, 0.11 mol) was reacted according to thesame procedures as Preparation 10 and Preparations 3 to 5 in the orderto give the title compound (5 g, Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 10.26 (br s, 1H), 8.05 (s, 1H), 7.69 (s, 1H),7.39 (m, 2H), 7.26 (s, 1H), 7.15 (m, 1H), 7.01 (m, 2H), 4.00 (s, 3H)

Preparation 13: Synthesis of7-nitro-5-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester

(Step 1)

1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g,0.38 mol) were dissolved in N,N-dimethylformamide (100 ml). Potassiumcarbonate (52.6 g, 0.38 mol) was added thereto, and the mixture wasstirred for 20 h at 100° C. Water was added to the reaction solution,which was then extracted with ethyl acetate. The extract was washed withsaturated sodium chloride solution, and dried over anhydrous magnesiumsulfate to give 3-(4-nitro-phenoxy)-pyridine.

The compound thus obtained was dissolved using water (100 ml),tetrahydrofuran (100 ml) and methanol (100 ml). Iron powder (103 g, 1.84mol) and ammonium chloride (99 g, 1.84 mol) were added thereto, and themixture was stirred using a mechanical stirrer for 3 h at 80° C. Aftercompletion of the reaction, the reaction solution was filtered through acelite, washed with methanol, and concentrated. The resulting solid wasfiltered, washed with ether, and dried to give4-(pyridin-3-yloxy)-phenylamine (17 g, Yield 36%).

(Step 2)

4-(Pyridin-3-yloxy)-phenylamine (25 g, 0.13 mol) prepared in Step 1 wasreacted according to the same procedures as Preparation 10 andPreparations 3 to 5 in the order to give the title compound (4.2 g,Yield 10%).

¹H-NMR (400 HMz, CDCl₃); δ 10.32 (br s, 1H), 8.51˜8.47 (m, 2H), 8.05 (d,J=2.4 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.42˜7.35 (m, 2H), 7.31 (d, J=2.4Hz, 1H), 4.48 (q, 2H), 1.47 (t, 3H)

Preparation 14: Synthesis of5-(4-methanesulfonyl-phenoxy)-7-nitro-1H-indole-2-carboxylic acid methylester

(Step 1)

1-Chloro-4-nitrobenzene (15 g, 95 mmol) and 4-(methylmercapto)phenol(13.3 g, 95 mmol) were dissolved in dimethylsulfoxide (100 ml).Potassium carbonate (15.8 g, 134 mmol) was added thereto, and themixture was stirred for 12 h at 100° C. After completion of thereaction, excess water was added to give precipitated solid. The solidwas filtered, and dried to give1-(4-methylsulfanylphenoxy)-4-nitrobenzene.

The compound thus obtained was dissolved in dichloromethane (500 ml).mCPBA (3-chloroperbenzoic acid) (83 g, 330 mmol) was added thereto, andthe mixture was stirred for 2 h at 0° C.˜room temperature. Aftercompletion of the reaction, excess 6N aqueous sodium hydroxide solutionwas added, and the mixture was extracted with ethyl acetate anddichloromethane. The extract was washed with saturated sodium chloridesolution, and dried over anhydrous magnesium sulfate to give1-(4-methylsulfonylphenoxy)-4-nitrobenzene (28 g, Yield 100%).

(Step 2)

1-(4-Methylsulfonylphenoxy)-4-nitrobenzene (28 g) prepared in Step 1 wasdissolved in methanol (500 ml) and ethyl acetate (500 ml). 10% Pd/C (1.0g) was added thereto, and the mixture was stirred for 3 h under hydrogengas of normal pressure. After completion of the reaction, the reactionsolution was filtered through a celite, washed with methanol,concentrated, and dried to give 4-(4-methanesulfonylphenoxy)-phenylamine(25 g, Yield 100%).

(Step 3)

4-(4-Methanesulfonylphenoxy)-phenylamine (25 g, 95 mmol) was reactedaccording to the same procedures as Preparation 10 and Preparations 3 to5 in the order to give the title compound (0.9 g, Yield 2.4%).

Preparation 15: Synthesis of(R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid methyl esterhydrochloride

(Step 1)

To a solvent mixture of diethylether (400 ml) and conc. hydrochloricacid (400 ml) was added in drops 4-methoxybenzylalcohol (280 g, 1780mmol) dissolved in diethylether (400 ml) for 2 h, and the mixture wasstirred for 1 h. The organic layer was separated, and added to asolution prepared by dissolving L-cysteine (197 g, 1625 mmol) and 2Naqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). Themixture was stirred for 2 h at room temperature. After completion of thereaction, the reaction solution was cooled to 0° C., and neutralized topH 7 using 3N aqueous hydrochloric acid solution. The resulting solidwas filtered, and dried to give(R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid (250 g, 1035mmol, Yield: 64%).

(Step 2)

The compound (30.7 g, 127.3 mmol) prepared in Step 1 was dissolved intetrahydrofuran (150 ml) and water (150 ml). Potassium carbonate (26.4g, 190 mmol) and di-t-butyloxy-dicarbonyl (27.7 g, 127.3 mmol) wereadded thereto, and the mixture was stirred for 2 h at room temperature.After completion of the reaction, the reaction solution was distilledunder reduced pressure to remove tetrahydrofuran. The residue was cooledto 0° C., and acidified to pH 3 using 3N aqueous hydrochloric acidsolution.

The resulting solid was washed with water, and dried to give(R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propionic acid(43 g, 126 mmol, Yield 99%).

(Step 3)

The compound (43 g) prepared in Step 2,1-methylmorpholine (14.5 ml, 132mmol) and ethylchloroformate (14.1 ml, 132 mmol) were dissolved intetrahydrofuran (500 ml), and stirred for 1 h at −25° C. Simultaneously,potassium hydroxide (75 g, 1336 mmol) was dissolved in water (75 ml) anddiethylether (750 ml), N-methyl-nitrosourea (26 g, 252 mmol) was addedin drops thereto for 2 h at 0° C., and the mixture was stirred for 30min. Thus prepared two solutions were mixed, and stirred for 3 h at −25°C.˜room temperature. After completion of the reaction, water was added,and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous ammonium chloride solution inthe order. The organic layer was concentrated to give[(R)-3-diazo-1-(4-methoxy-benzylsulfanylmethyl)-2-oxo-propyl]-carbamicacid t-butyl ester.

¹H-NMR (400 HMz, CDCl₃); δ 7.25 (d, J=8.8 Hzm 2H), 6.86 (d, J=8.8 Hz,2H), 5.48 (br s 1H), 5.29 (m, 1H), 4.31 (m, 1H), 3.79 (s, 3H), 3.69 (s,2H), 2.76 (d, J=6.0 Hz, 2H), 1.45 (s, 9H)

(Step 4)

The compound prepared in Step 3 was dissolved in methanol (1000 ml),silver benzoate (7.1 g, 31.1 mmol) was added thereto, and the mixturewas sonicated for 1 h. After completion of the reaction, the reactionsolution was concentrated, and separated by column chromatography togive (R)-3-t-butoxycarbonylamino-4-(4-methoxy-benzylsulfanyl)-butyricacid methyl ester (35.2 g, 95.3 mmol, Yield 76%).

¹H-NMR (500 HMz, CDCl₃); δ 7.24 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz,2H), 5.09 (m, 1H), 4.08 (m, 1H), 3.79 (s, 3H), 3.68 (s, 2H), 3.66 (s,3H), 2.70-2.52 (m, 4H), 1.44 (s, 9H)

(Step 5)

The compound (35.2 g) prepared in Step 4 was dissolved indichloromethane (70 ml), 4N hydrochloric acid/1,4-dioxane solution (71ml) was added thereto, and the mixture was stirred for 2 h at roomtemperature. After completion of the reaction, the reaction solution wasconcentrated. Dichloromethane (30 ml) and diethylether (150 ml) wereadded to the residue, and the resulting solid was filtered and dried togive the title compound (25.5 g, 83.3 mmol, Yield 87%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.21 (br s, 3H), 7.25 (d, 2H), 6.83 (d,2H), 3.78 (s, 3H), 3.68 (s, 2H), 3.65 (s, 3H), 3.29 (m, 1H), 2.51˜2.48(m, 2H), 2.35˜2.31 (m, 2H)

Preparation 16: Synthesis of(R)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid ethyl esterhydrochloride

L-cysteine (50 g, 0.41 mol) was reacted according to the same procedureas Preparation 15 except that ethanol was used instead of methanol inStep 4 of Preparation 15 to give the title compound (5.2 g, Yield 40%).

¹H NMR (400 MHz, CDCl₃); δ 8.37 (br s, 3H), 7.28 (d, J=8.0 Hz, 2H), 6.87(d, J=8.0 Hz, 2H), 4.11 (m, 2H), 3.73 (s, 3H), 3.70 (s, 2H), 2.81˜2.67(m, 4H), 1.18 (t, 3H)

Preparation 17: Synthesis of(R)-4-amino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid ethyl esterhydrochloride

(Step 1)

(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid ethyl ester (36 g,137.8 mmol) that can be obtained by a known method and triethylamine(38.4 ml, 275.5 mol) were dissolved in dichloromethane (200 ml).Methanesulfonylchloride (11.7 ml, 151.5 mmol) was added in dropsthereto, and the mixture was stirred for 1 h at 0° C.˜room temperature.1N hydrochloric acid solution was added thereto, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedsodium chloride solution, and dried over anhydrous magnesium sulfate togive (R)-4-t-butoxycarbonylamino-5-methanesulfonyloxy-pentanoic acidethyl ester.

(Step 2)

Sodium hydride (5.5 g, 137.8 mmol) and 4-methoxybenzylmercaptan (15.4ml, 110.2 mmol) were dissolved in N,N-dimethylformamide (150 ml), andstirred for 10 min at 0° C. To thus obtained solution was added in dropsthe methanesulfonate prepared in Step 1. The mixture was stirred for 4 hat 0° C. After completion of the reaction, water was added, and thereaction solution was extracted with ethyl acetate. The extract waswashed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and separated by column chromatography to give(R)-4-t-butoxycarbonylamino-5-(4-methoxy-benzylsulfanyl)-pentanoic acidethyl ester (21.0 g, Yield 38%).

¹H-NMR (400 HMz, CDCl₃); δ 7.25 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz,2H), 4.56 (m, 1H), 4.12 (m, 2H), 3.79 (s, 3H), 3.69 (s, 2H), 2.53 (m,2H), 2.33 (t, 2H), 1.93 (m, 1H), 1.70 (m, 1H), 1.44 (s, 9H), 1.25 (t,3H)

(Step 3)

The compound (11 g, 62.7 mmol) prepared in Step 2 was dissolved indichloromethane (200 ml), and 4N hydrochloric acid/ethyl acetatesolution (20 ml) was added thereto. The mixture was stirred for 2 h atroom temperature. After completion of the reaction, the reactionsolution was thoroughly concentrated, and diethylether (150 ml) wasadded thereto. The resulting solid was filtered and dried to give thetitle compound (20 g, Yield 96%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.69 (br s, 3H), 7.29 (d, J=8.0 Hz, 2H),6.89 (d, J=8.0 Hz, 2H), 4.08 (m, 2H), 3.74 (m, 5H), 3.26 (m, 1H),2.76˜2.63 (m, 2H), 2.49˜2.40 (m, 2H), 1.89 (m, 2H), 1.20 (t, 3H)

Preparation 18: Synthesis of 2,2-dimethyl-propionic acid(R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propyl ester

(Step 1)

The compound (50 g, 207.2 mmol) prepared in Step 1 of Preparation 15 wasdissolved in methanol (300 ml). Acetyl chloride (21 ml, 207.2 mmol) wasadded in drops thereto, and stirred for 12 h at 50° C. After completionof the reaction, the reaction solution was thoroughly concentrated, towhich was added diethylether. The resulting solid was filtered and driedto give (R)-2-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid methylester.

¹H NMR (400 MHz, DMSO-d₆, HCl salt); δ 8.81 (br s, 3H), 7.29 (d, J=8.4Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 4.28 (m, 1H), 3.18 (br s, 8H), 2.95 (m,2H)

(Step 2)

The compound prepared in Step 1 was dissolved in tetrahydrofuran (200ml) and water (200 ml). Triethylamine (87 ml, 621.6 mmol) was addedthereto, and di-t-butyloxy-dicarbonyl (43.0 g, 196.8 mmol) dissolved intetrahydrofuran (100 ml) was added in drops thereto while stirring. Themixture was stirred for 8 h at room temperature. After completion of thereaction, water was added to the reaction solution, which was thenextracted with ethyl acetate. The extract was washed with saturatedsodium chloride solution, and dried over anhydrous magnesium sulfate togive (R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propionicacid methyl ester.

(Step 3)

The compound prepared in Step 2 was dissolved in tetrahydrofuran (300ml). Lithium borohydride (9.0 g, 414.4 mmol) was added thereto, and themixture was stirred for 3 h at 0° C. After completion of the reaction,water was added, and the reaction solution was extracted with ethylacetate. The extract was washed with saturated sodium chloride solutionand dried over anhydrous magnesium sulfate to give[(R)-2-hydroxy-1-(4-methoxy-benzylsulfanylmethyl)-ethyl]-carbamic acidt-butyl ester.

¹H NMR (500 MHz, DMSO-d₆); δ 7.24 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz,2H), 4.96 (br s, 1H), 3.78 (s, 3H), 3.76 (br s, 1H), 3.70 (s, 2H),3.7˜3.66 (m, 3H), 2.58 (m, 2H), 1.44 (s, 9H)

(Step 4)

The compound prepared in Step 3 was dissolved in dichloromethane (300ml). Triethylamine (58 ml, 414.4 mmol) and trimethylacetyl chloride (28ml, 227.9 mmol) were added thereto, and the mixture was stirred for 6 hat 0° C. After completion of the reaction, water was added, and thereaction solution was extracted with ethyl acetate. The extract waswashed with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate, and separated by column chromatography to give2,2-dimethyl-propionic acid(R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propyl ester(81.0 g, Yield 95%).

¹H NMR (400 MHz, CDCl₃); δ 7.25 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz,2H), 4.71 (m, 1H), 4.11 (m, 2H), 3.79 (s, 3H), 3.70 (s, 2H), 2.55 (d,J=6.4 Hz, 2H), 1.52 (s, (H, 1.27 (s, 9H)

(Step 5)

The compound (81 g, 196 mmol) prepared in Step 4 was dissolved indichloromethane (300 ml). 4N hydrochloric acid/1,4-dioxane solution (100ml) was added thereto, and the mixture was stirred for 8 h at roomtemperature. After completion of the reaction, the reaction solution wasthoroughly concentrated, and diethylether was added. The resulting solidwas filtered and dried to give the title compound (68 g, Yield 95%).

¹H NMR (400 MHz, DMSO-d₆, free form); δ 7.24 (d, J=12.0 Hz, 2H), 6.85(dd, J=4.0, 8.0 Hz, 2H), 4.04 (m, 1H), 3.95 (m, 1H), 3.80 (s, 3H), 3.68(s, 2H), 3.10 (m, 1H), 2.60 (m, 1H), 2.36 (m, 1H), 1.18 (s, 9H)

Preparation 19: Synthesis of 2,2-dimethyl-propionic acid(R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester

(Step 1)

Methyl 7-nitroindole-2-carboxylate (13 g, 59 mmol) prepared inPreparation 8 was dissolved in a solvent mixture of tetrahydrofuran andwater (1:1, 300 ml), and 1N aqueous sodium hydroxide solution (180 ml,177 mmol) was added thereto. The mixture was stirred for 3 h at roomtemperature, excess 6N hydrochloric acid solution was added, and themixture was extracted with ethyl acetate. The extract was washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reduced pressureto give 7-nitro-1H-indole-2-carboxylic acid (12 g, Yield 99%).

(Step 2)

7-Nitroindole-carboxylic acid compound (8.2 g, 22.7 mmol) prepared inStep 1 and the amine compound (13.2 g, 27.2 mmol) prepared inPreparation 18 were dissolved in N,N-dimethylformamide (100 ml), and EDC(6.6 g, 25.0 mmol) and HOBT (4.6 g, 25.0 mmol) were added thereto. Themixture was stirred for 8 h at room temperature, and saturated sodiumbicarbonate solution was added thereto. The mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, concentrated, and theresidue was purified by column chromatography to give2,2-dimethyl-propionic acid(R)-3-(4-methoxy-benzylsulfanyl)-2-[(7-nitro-1H-indole-2-carbonyl)-amino-propylester (8.1 g, Yield 71%).

¹H-NMR (400 HMz, CDCl₃); δ 10.47 (br s, 1H), 8.27 (d, J=8.0 Hz, 1H),8.01 (d, J=8.0 Hz, 1H), 7.26 (m, 2H), 6.93 (d, J=4.0 Hz, 1H), 6.83 (m,2H), 6.74 (d, J=8.0 Hz, 1H), 4.56 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H),3.74 (m, 5H), 2.77 (m, 1H), 2.62 (m, 1H), 1.18 (s, 9H)

(Step 3)

The compound (1.6 g, 3.2 mmol) prepared in Step 2 was dissolved indichloromethane (50 ml). Phosphorus pentachloride (1.3 g, 6.4 mmol) wasadded thereto, and the mixture was stirred for 5 h at room temperature.After completion of the reaction, saturated sodium bicarbonate solutionwas added thereto. The mixture was extracted with ethyl acetate, driedover anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, concentrated, and the residue waspurified by column chromatography to give 2,2-dimethyl-propionic acid(R)-2-(7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethyl ester (0.8g, Yield 69%).

¹H-NMR (400 HMz, CDCl₃); δ 10.53 (br s, 1H), 8.26 (d, J=8.0 Hz, 1H),7.99 (d, J=8.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H),4.78 (m, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 3.59 (m, 1H), 3.36 (m, 1H),1.20 (s, 9H)

(Step 4)

The compound (2.7 g, 7.5 mmol) prepared in Step 3 was dissolved in asolvent mixture of tetrahydrofuran, methanol and water (1:1:1, 150 ml).Iron powder (4.2 g, 74.7 mmol) and ammonium chloride (4.0 g, 74.7 mmol)were added, and the mixture was stirred for 30 min at 60° C. using amechanical stirrer. After completion of the reaction, water was addedthereto. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure, and purified by column chromatography to givethe title compound (2.0 g, Yield 81%).

¹H-NMR (400 HMz, CDCl₃); δ 9.86 (br s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.14(d, J=8.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.61 (dd, J=0.8, 7.2 Hz, 1H),4.96 (m, 1H), 4.36 (m, 2H), 3.55 (m, 1H), 3.33 (m, 1H), 1.18 (s, 9H)

Preparation 20: Synthesis of 2,2-dimethyl-propionic acid(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethylester

The compound (2.0 g, 5.0 mmol) prepared in Preparation 19 was dissolvedin 1,2-dichloroethane (100 ml). Cyclopentanone (0.8 g, 7.5 mmol) andsodium triacetoxyborohydride (1.9 g, 7.5 mmol) were added thereto, andthe mixture was stirred for 8 h at room temperature. After completion ofthe reaction, water was added thereto. The mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and the residue waspurified by column chromatography to give the title compound (1.3 g,Yield 54%).

Example 1 Synthesis of[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol

The compound (1.3 g, 3.3 mmol) prepared in Preparation 20 was dissolvedin tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). Lithiumhydroxide hydrate (0.4 g, 9.8 mmol) was added thereto, and the mixturewas stirred for 4 h at room temperature. The reaction solution wasconcentrated by distillation under reduced pressure. 1N hydrochloricacid was added to the residue, which was then extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give the title compound (820 mg, Yield 80%).

¹H-NMR (500 HMz, CDCl₃); δ 11.17˜11.08 (m, 1H), 7.09 (m, 1H), 6.99 (t,1H), 6.96 (s, 1H), 6.52 (m, 1H), 4.72 (m, 1H), 4.04 (m, 1H), 3.75 (m,1H), 3.65 (m, 1H), 3.51 (m, 1H), 3.40 (m, 1H), 1.90 (m, 2H), 1.60-1.49(m, 4H), 1.41-1.24 (m, 2H)

Mass Spectrum (ESI, m/z): Calculated 315.14. Found 315.44

Example 2 Synthesis of{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

(Step 1)

The compound (900 mg, 2.7 mmol) prepared in Preparation 19 was dissolvedin 1,2-dichloroethane (100 ml). Tetrahydro-4H-pyran-4-one (0.8 ml, 8.13mmol), sodium triacetoxyborohydride (1.72 g, 8.13 mmol) and acetic acid(0.47 ml, 8.13 mmol) were added thereto, and the mixture was stirred for48 h at room temperature. After completion of the reaction, the reactionsolution was diluted with dichloromethane, washed with saturated sodiumbicarbonate solution, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was distilled under reduced pressure, andpurified by column chromatography to give 2,2-dimethylpropionic acid(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethylester.

¹H-NMR (400 HMz, CDCl₃); δ 10.91 (br s, 1H), 7.01˜6.91 (m, 3H), 6.48 (d,J=7.2 Hz, 1H), 4.86 (m, 1H), 4.34 (m 2H), 4.00 (m, 2H), 3.61 (m, 1H),3.54 (m, 3H), 3.31 (m, 1H), 2.05 (m, 2H), 1.55 (m, 2H), 1.16 (s, 9H)

(Step 2)

The compound prepared in Step 1 was dissolved in methanol (32 ml),tetrahydrofuran (32 ml) and water (16 ml). 1N sodium hydroxide (7 ml)was added thereto, and the mixture was stirred for 4 h at roomtemperature. After completion of the reaction, the reaction solution wasdistilled under reduced pressure, extracted with dichloromethane, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (700 mg, Yield 78%).

¹H-NMR (500 HMz, CDCl₃); δ 11.04˜10.95 (m, 1H), 7.11 (m, 1H), 6.99 (t,1H), 6.96 (s, 1H), 6.52 (m, 1H), 4.74 (m, 1H), 4.02 (m, 1H), 3.92 (m,2H), 3.68 (m, 1H), 3.46˜3.30 (m, 5H), 1.91 (m, 2H), 1.28 (m, 2H)

Mass Spectrum (ESI, m/z): Calculated 331.14. Found 331.44

Example 3 Synthesis of{(R)-2-[7-(tetrahydro-furan-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The compound (940 mg, 2.9 mmol) prepared in Preparation 19 andtetrahydrofuran-3-one instead of tetrahydro-4H-pyran-4-one were reactedaccording to the same procedure as Example 2 to give the title compound(650 mg, Yield 69%).

¹H-NMR (500 HMz, CDCl₃); δ 10.58 (br s, 1H), 7.14 (d, J=7.95 Hz, 1H),7.00 (m, 1H), 6.94 (m, 1H), 6.48 (d, J=7.35 Hz, 1H), 4.79 (m, 1H),4.15˜3.95 ((m, 3H), 3.90˜3.65 (m, 4H), 3.50˜3.39 (m, 2H), 2.20 (m, 1H),1.83 (m, 1H)

Example 4 Synthesis of{(R)-2-[7-(1-methanesulfonyl-pyrrolidin-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

(Step 1)

The compound (1.0 mg, 3.0 mmol) prepared in Preparation 19 and3-oxo-pyrrolidine-1-carboxylicacid t-butyl ester (1.1 g, 6.0 mmol)instead of tetrahydro-4H-pyran-4-one were reacted according to the sameprocedure as Step 1 of Example 2 to give a pyrrolidine compound (853 mg,Yield 57%).

(Step 2)

The compound (460 mg, 0.9 mmol) prepared in Step 1 was dissolved inmethanol (50 ml), and 4N hydrochloric acid solution (0.8 ml, 2.7 mmol)was added thereto. The mixture was stirred for 8 h at room temperature,distilled under reduced pressure, and purified by column chromatography.

Thus purified compound (313 mg, 0.8 mmol) was dissolved indichloromethane (50 ml). Triethylamine (158 mg, 1.6 mmol) andmethanesulfonyl chloride (90 mg, 0.8 mmol) were added, and the mixturewas stirred for 30 min at 0° C.˜room temperature. After completion ofthe reaction, water was added to the reaction solution, which was thenextracted with dichloromethane, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give a sulfonamide compound (223 mg, Yield 58%).

(Step 3)

The compound (223 mg, 0.47 mmol) prepared in Step 2 was reactedaccording to the same procedure as Example 1 to give the title compound(152 mg, Yield 82%).

¹H-NMR (500 HMz, CDCl₃); δ 10.50 (br s, 1H), 7.15 (d, J=7.95 Hz, 1H),7.00 (dd, 1H), 6.93 (s, 1H), 6.46 (d, J=7.35 Hz, 1H), 4.77 (m, 1H), 4.18(m, 1H), 4.08 (dd, 1H), 3.75 (dd, 1H), 3.59˜3.36 (m, 6H), 3.48 (s, 3H),2.27 (m, 1H), 1.95 (m, 1H)

Preparation 21: Synthesis of 2,2-dimethyl-propionic acid(R)-2-[7-amino-5-fluoro-1H-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethylester

Ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate (6.0 g, 23.8 mmol)prepared in Preparation 2 was reacted according to the same procedure asPreparation 19 to give the title compound (2.3 g, Yield 28%).

Example 5 Synthesis of[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

The amine compound (1.1 g, 3.1 mmol) prepared in Preparation 21 wasreacted according to the same procedures as Preparation 20 and Example 1to give the title compound (600 mg, Yield 58%).

¹H-NMR (400 HMz, CDCl₃); δ 10.73 (br s, 1H), 6.91 (s, 1H), 6.72 (m, 1H),6.33 (m, 1H), 4.78 (m, 1H), 4.12 (m, 1H), 3.97 (br s, 1H), 3.79 (m, 1H),3.75 (m, 1H), 3.49 (m, 2H), 2.01 (m, 2H), 1.62 (m, 4H), 1.41 (m, 2H)

Example 6 Synthesis of{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The amine compound (1.1 g, 3.1 mmol) prepared in Preparation 21 wasreacted according to the same procedure as Example 2 to give the titlecompound (750 mg, Yield 68%).

¹H-NMR (400 HMz, CDCl₃); δ 10.45 (br s, 1H), 6.90 (s, 1H), 6.75 (m, 1H),6.34 (m, 1H), 4.82 (m, 1H), 4.12 (m, 1H), 4.01 (m, 2H), 3.94 (m, 1H),3.78 (m, 1H), 3.54˜3.43 (m, 5H), 2.03 (m, 2H), 1.50 (m, 2H)

Example 7 Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

(Step 1)

Methyl 5-chloro-7-nitro-1H-indole-2-carboxylate (3.0 g, 11.8 mmol)prepared in Preparation 5 was reacted according to the same procedure asPreparation 19 to give an amine compound (2.4 g, Yield 56%).

(Step 2)

The amine compound (150 mg, 0.4 mmol) prepared in Step 1 was reactedaccording to the same procedures as Preparation 20 and Example 1 to givethe title compound (50 mg, Yield 36%).

¹H-NMR (500 HMz, CDCl₃); δ 10.53 (br s, 1H), 7.24 (s, 1H), 6.84 (d, 1H),6.45 (s, 1H), 4.74 (m, 1H), 4.06 (m, 1H), 3.81 (m, 1H), 3.71 (m, 1H),3.45 (dd, 2H), 1.99 (m, 2H), 1.60 (m, 4H), 1.37 (m, 2H)

Example 8 Synthesis of{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The amine compound (150 mg, 0.4 mmol) prepared in Step 1 of Example 7was reacted according to the same procedure as Example 2 to give thetitle compound (40 mg, Yield 27%).

Example 9 Synthesis of{(R)-2-[5-chloro-7-(tetrahydro-thiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The amine compound (150 mg, 0.4 mmol) prepared in Step 1 of Example 7and tetrahydro-thiopyran-4-one instead of tetrahydro-4H-pyran-4-one werereacted according to the same procedure as Example 2 to give the titlecompound (130 mg, Yield 85%).

¹H-NMR (400 HMz, CDCl₃); δ 10.87 (br s, 1H), 7.01 (s, 1H), 6.89 (s, 1H),6.40 (s, 1H), 4.80 (m, 1H), 4.10 (m, 1H), 3.80 (m, 1H), 3.50 (m, 2H),3.32 (m, 1H), 2.76 (m, 4H), 2.29 (m, 2H), 1.56 (m, 2H)

Example 10 Synthesis of[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

Methyl 5-bromo-7-nitro-1H-indole-2-carboxylate (1.3 g, 4.3 mmol)prepared in Preparation 6 was reacted according to the same proceduresas Preparation 19, Preparation 20 and Example 1 in the order to give thetitle compound (100 mg, Yield 6%).

¹H-NMR (400 HMz, CDCl₃); δ 10.59 (br s, 1H), 7.23 (s, 1H), 6.88 (s, 1H),6.64 (d, 1H), 4.77 (m, 1H), 4.14 (m, 1H), 3.82 (m, 1H), 3.76 (m, 1H),3.49 (dd, 2H), 2.04 (m, 2H), 1.65 (m, 4H), 1.41 (m, 2H)

Example 11 Synthesis of{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

Methyl 5-bromo-7-nitro-1H-indole-2-carboxylate (1.3 g, 4.3 mmol)prepared in Preparation 6 was reacted according to the same proceduresas Preparation 19 and Example 2 in the order to give the title compound(70 mg, Yield 4%).

¹H-NMR (400 HMz, CDCl₃); δ 10.53 (br s, 1H), 7.25 (s, 1H), 6.87 (s, 1H),6.63 (d, 1H), 4.80 (m, 1H), 4.14 (m, 1H), 4.03 (m, 2H), 3.79 (m, 1H),3.56-3.3.44 (m, 4H), 2.02 (m, 2H), 1.45 (m, 2H)

Example 12 Synthesis of[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

Methyl 5-methoxy-7-nitro-1H-indole-2-carboxylate (700 mg, 2.8 mmol)prepared in Preparation 9 was reacted according to the same proceduresas Preparation 19, Preparation 20 and Example 1 in the order to give thetitle compound (80 mg, Yield 8%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.23 (br s, 1H), 6.60 (s, 1H), 6.23 (s,1H), 5.89 (m, 1H), 5.84 (m, 1H), 4.96 (m, 1H), 4.65 (m, 1H), 3.77 (m,1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.33 (m, 1H), 3.29 (s, 3H), 1.91 (m,2H), 1.67 (m, 2H), 1.53 (m, 4H)

Example 13 Synthesis of{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

7-Nitro-5-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (500mg, 1.5 mmol) prepared in Preparation 13 was reacted according to thesame procedures as Preparation 19, Preparation 20 and Example 1 in theorder to give the title compound (35 mg, Yield 6%).

¹H-NMR (400 HMz, CDCl₃); δ 11.16 (br s, 1H), 8.42 (d, 1H), 8.28 (m, 1H),7.30 (m, 1H), 7.22 (m, 1H), 6.88 (s, 1H), 6.67 (d, 1H), 6.28 (d, 1H),4.83 (m, 1H), 4.02 (m, 1H), 3.75 (m, 2H), 3.46 (m, 2H), 1.97 (m, 2H),1.63 (m, 4H), 1.43 (m, 2H)

Example 14 Synthesis of{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

7-Nitro-5-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (500mg, mmol) prepared in Preparation 13 was reacted according to the sameprocedures as Preparation 19 and Example 2 in the order to give thetitle compound (40 mg, Yield 6%).

¹H-NMR (400 HMz, CDCl₃); δ 10.96 (br s, 1H), 8.36 (d, J=2.4 Hz, 1H),8.26 (m, 1H), 7.27 (m, 1H), 7.19 (m, 1H), 6.83 (s, 1H), 6.63 (d, J=1.6Hz, 1H), 6.24 (d, J=1.6 Hz, 1H), 4.81 (m, 1H), 4.01-3.94 (m, 3H), 3.75(m, 1H), 3.47 (s, 3H), 3.48-3.29 (m, 5H), 1.93 (m, 2H), 1.52 (m, 2H)

Preparation 22: Synthesis of methanesulfonic acid(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethylester

The compound (820 mg, 2.6 mmol) prepared in Example 1 was dissolved indichloromethane (50 ml). Methanesulfonyl chloride (0.24 ml, 3.1 mmol)and triethylamine (0.81 ml, 3.1 mmol) were added thereto, and themixture was stirred for 30 min at 0° C. After completion of thereaction, saturated sodium bicarbonate solution was added, and themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (600 mg, Yield 60%).

Example 15 Synthesis ofcyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

The compound (150 mg, 0.38 mmol) prepared in Preparation 22 wasdissolved in N,N-dimethylformamide (5 ml). Pyrrolidine (0.08 ml, 1.1mmol) was added thereto, and the mixture was stirred for 4 h at 70° C.After completion of the reaction, water was added, which was thenextracted with ethyl acetate, dried over anhydrous magnesium sulfate,and filtered. The filtrate was distilled under reduced pressure, andpurified by column chromatography to give the title compound (20 mg,Yield 14%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.37 (br s, 1H), 6.83 (m, 1H), 6.75 (d,J=2.0 Hz, 1H), 6.29 (d, J=8.0 Hz, 1H), 5.86 (d, J=8.0 Hz, 1H), 4.80 (m,1H), 3.87 (m, 1H), 3.52 (m, 1H), 3.43 (m, 1H), 3.33 (m, 2H), 2.78 (m,2H), 2.61 (m, 2H), 1.99 (m, 2H), 1.72 (m, 6H), 1.60 (m, 4H)

Example 16 Synthesis ofcyclopentyl-[2((R)-4-morpholin-4-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

The compound (150 mg, 0.38 mmol) prepared in Preparation 22 andmorpholine instead of pyrrolidine were reacted according to the sameprocedure as Example 15 to give the title compound (50 mg, Yield 34%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.37 (br s, 1H), 6.83 (m, 1H), 6.75 (m,1H), 6.29 (d, J=8.0 Hz, 1H), 5.85 (d, J=8.0 Hz, 1H), 4.87 (m, 1H), 3.87(m, 1H), 3.61 (m, 4H), 3.35 (m, 3H), 2.71 (m, 1H), 2.54 (m, 2H), 2.44(m, 2H), 1.99 (m, 2H), 1.74 (m, 6H), 1.59 (m, 4H)

Example 17 Synthesis ofcyclopentyl-[2((R)-4-dimethylaminomethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine

The compound (150 mg, 0.38 mmol) prepared in Preparation 22 anddimethylamine instead of pyrrolidine were reacted according to the sameprocedure as Example 15 to give the title compound (20 mg, Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 9.87 (br, 1H), 7.05 (d, J=8.0 Hz, 1H), 6.99(t, 1H), 6.89 (s, 1H), 6.52 (d, J=8.0 Hz, 1H), 4.83 (m, 1H), 3.91 (m,1H), 3.50 (t, 1H), 3.29 (t, 1H), 2.63 (m, 1H), 2.44 (m, 1H), 2.29 (s,6H), 2.04 (m, 2H), 1.70 (m, 2H), 1.50 (m, 4H)

Example 18 Synthesis of2-[2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-ylamino]-propionicacid

The compound prepared in Preparation 19 and methyl pyruvate were reactedaccording to the same procedures as Preparation 20 and Example 1consecutively to give the title compound.

¹H-NMR (400 HMz, CDCl₃); δ 11.16 (m, 1H), 10.43 (br, 1H), 7.04 (m, 1H),7.00 (m, 1H), 6.97 (m, 1H), 6.53 (m, 1H), 4.74 (m, 1H), 4.14 (m, 1H),4.05 (m, 1H), 3.77 (m, 1H), 3.57 (m, 1H), 3.42 (m, 1H), 1.43 (d, 3H)

Example 19 Synthesis of{(R)-2-[7-(4-nitro-phenylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The compound prepared in Preparation 19 and 4-fluoro-nitrobenzene werereacted in the presence of a base Cs₂CO₃ according to the same procedureas Example 15 to give the title compound.

¹H-NMR (400 HMz, CDCl₃); δ 11.15 (br, 1H), 7.85 (d, 2H), 7.04 (m, 1H),6.97 (m, 1H), 6.96 (m, 1H), 6.65 (d, 2H), 6.53 (m, 1H), 4.73 (m, 1H),4.10 (m, 1H), 3.78 (m, 1H), 3.52 (m, 1H), 3.38 (m, 1H)

Preparation 23: Synthesis of 5-methyl-7-nitro-indole-1,2-dicarboxylicacid 1-t-butyl ester 2-methyl ester

The compound (24.0 g, 100 mmol) prepared in Preparation 7 was dissolvedin dichloromethane (500 ml). Triethylamine (84 ml, 601 mmol) and4-(dimethylamino)pyridine (600 mg, 5 mmol) were added, anddi-t-butyloxy-dicarbonyl (43.7 g, 200 mmol) dissolved in dichloromethane(100 ml) was added in drops thereto. The mixture was stirred for 8 h atroom temperature. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, washed with saturated sodiumchloride solution, and dried over anhydrous magnesium sulfate to givethe title compound (34.0 g, Yield 100%).

¹H-NMR (500 HMz, CDCl₃); δ 7.80 (s, 1H), 7.67 (s, 1H), 7.15 (s, 1H),3.93 (s, 3H), 2.51 (s, 3H), 1.62 (s, 9H)

Preparation 24: Synthesis of5-bromomethyl-7-nitro-indole-1,2-dicarboxylic acid 1-t-butyl ester2-methyl ester

The compound (34 g, 101.7 mmol) prepared in Preparation 23 was dissolvedin carebon tetrachloride (100 ml). N-bromosuccinimide (27.2 g, 152.6mmol) and AIBN (1.7 g, 10.2 mmol) were added thereto, and the mixturewas stirred for 5 h at 80° C. After completion of the reaction, thereaction solution was distilled under reduced pressure, and purified bycolumn chromatography to give the title compound (48.0 g, Yield 100%).

¹H-NMR (500 HMz, CDCl₃); δ 8.01 (s, 1H), 7.90 (s, 1H), 7.21 (s, 1H),4.60 (s, 2H), 3.93 (s, 3H), 1.62 (s, 9H)

Preparation 25: Synthesis of5-acetoxymethyl-7-nitro-indole-1,2-dicarboxylic acid 1-t-butyl ester2-methyl ester

The compound (10.0 g, 24.2 mmol) prepared in Preparation 24 wasdissolved in N,N-dimethylformamide (50 ml). Sodium acetate (2.4 g, 29.0mmol) was added thereto, and the mixture was stirred for 4 h at roomtemperature. After completion of the reaction, the reaction solution wasdistilled under reduced pressure. Water was added, and the mixture wasextracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and purified by columnchromatography to give the title compound (4.7 g, Yield 50%).

¹H-NMR (500 HMz, CDCl₃); δ 7.99 (s, 1H), 7.90 (s, 1H), 7.21 (s, 1H),5.22 (s, 2H), 3.94 (s, 3H), 2.12 (s, 3H), 1.63 (s, 9H)

Preparation 26: Synthesis of5-acetoxymethyl-7-nitro-1H-indole-2-carboxylic acid methyl ester

The compound (4.7 g, 12.0 mmol) prepared in Preparation 25 was dissolvedin dichloromethane (50 ml). 2N hydrochloric acid solution (30 ml, 60mmol) was added thereto, and the mixture was stirred for 12 h at roomtemperature and distilled under reduced pressure to give the titlecompound (3.5 g, Yield 100%) as a solid.

¹H-NMR (500 HMz, CDCl₃); δ 10.33 (br s, 1H), 8.32 (s, 1H), 8.06 (s, 1H),7.34 (s, 1H), 5.24 (s, 2H), 3.99 (s, 3H), 2.12 (s, 3H)

Preparation 27: Synthesis of5-hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid

The compound (3.5 g, 12.0 mmol) prepared in Preparation 26 was dissolvedin a solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 100ml). Lithium hydroxide hydrate (1.5 g, 35.9 mmol) was added thereto, andthe mixture was stirred for 3 h at room temperature. After distillationof the mixture under reduced pressure, 1 N hydrochloric acid was addedto the residue. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure and purified by column chromatography to give thetitle compound (2.3 g, Yield 81%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.02 (br s, 1H), 8.21 (s, 1H), 8.10 (s,1H), 7.34 (s, 1H), 5.43 (br s, 1H), 4.64 (s, 2H)

Preparation 28: Synthesis of 2,2-dimethyl-propionic acid(R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)-amino]-3-(4-methoxy-benzylsulfanyl)-propylester

The compound (2.2 g, 9.3 mmol) prepared in Preparation 27 was reactedaccording to the same procedure as Step 2 of Preparation 19 to give thetitle compound (4.0 g, Yield 84%).

Preparation 29: Synthesis of 2,2-dimethyl-propionic acid(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethylester

The compound (1.0 g, 1.9 mmol) prepared in Preparation 28 was dissolvedin dichloromethane (30 ml). Phosphorus pentachloride (0.8 g, 3.9 mmol)was added thereto, and the mixture was stirred for 6 h at roomtemperature. After completion of the reaction, saturated sodiumbicarbonate solution was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure to give the title compound(0.7 g, Yield 90%).

¹H-NMR (500 HMz, CDCl₃); δ 12.89 (br s, 1H), 8.40 (s, 1H), 7.98 (s, 1H),7.42 (s, 1H), 5.30 (m, 1H), 4.73 (s, 2H), 4.61 (m, 1H), 4.54 (m, 1H),3.97 (m, 1H), 3.62 (m, 1H), 1.20 (s, 9H)

Example 20 Synthesis of{(R)-2-[5-morpholin-4-ylmethyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The compound prepared in Preparation 29, morpholine andtetrahydropyran-4-one were reacted according to the same procedures asExample 15, Preparation 20 and Example 1 in the order to give the titlecompound (20 mg, Yield 12%).

¹H-NMR (400 HMz, CDCl₃); δ 10.77 (br s, 1H), 7.06 (s, 1H), 6.95 (s, 1H),6.62 (s, 1H), 4.80 (m, 1H), 4.11 (m, 1H), 3.99 (m, 2H), 3.76 (m, 1H),3.75 (m, 4H), 3.51 (s, 2H), 3.45 (m, 5H), 2.51 (br s, 4H), 2.00 (m, 2H),1.45 (m, 2H)

Example 21 Synthesis of[(R)-2-[7-cyclopentylamino-5-pyrazol-1-ylmethyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

(Step 1)

The compound (300 mg, 0.73 mmol) prepared in Preparation 29 wasdissolved in N,N-dimethylformamide (10 ml). Potassium carbonate (300 mg,2.2 mmol) and pyrazole (149 mg, 2.2 mmol) were added thereto, and themixture was stirred for 1 h at room temperature. After completion of thereaction, water was added, and the mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure to give a pyrazolecompound (225 mg, Yield 70%).

(Step 2)

The compound (300 mg, 0.68 mmol) prepared in Step 1 was reactedaccording to the same procedures as Step 4 of Preparation 19,Preparation 20 and Example 1 in the order to give the title compound (42mg, Yield 24%).

¹H-NMR (500 HMz, CDCl₃); δ 11.05 (brs, 1H), 7.52 (s, 1H), 7.34 (s, 1H),6.93 (s, 1H), 6.87 (s, 1H), 6.34 (s, 1H), 6.23 (m, 1H), 5.30 (s, 2H),4.71 (m, 1H), 3.99 (m, 1H), 3.66 (m, 2H), 3.42 (m, 2H), 1.86 (m, 2H),1.52 (m, 4H), 1.26 (m, 2H)

Example 22 Synthesis of[(R)-2-(7-cyclopentylamino-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl}-methanol

The compound (300 mg, 0.73 mmol) prepared in Preparation 29 andimidazole instead of pyrazole were reacted according to the sameprocedure as Example 21 to give the title compound (65 mg, Yield 23%).

¹H-NMR (500 HMz, CDCl₃); δ 11.10 (brs, 1H), 8.20 (s, 1H), 7.25 (s, 1H),7.23 (s, 1H), 6.87 (m, 2H), 6.16 (s, 1H), 5.05 (s, 2H), 4.77 (m, 1H),3.96 (m, 1H), 3.73 (m, 2H), 3.43 (m, 2H), 1.92 (m, 2H), 1.59 (m, 4H),1.38 (m, 2H)

Example 23 Synthesis of{(R)-2-[7-cyclopentylamino-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol

The compound (300 mg, 0.73 mmol) prepared in Preparation 29 and pyrroleinstead of pyrazole were reacted according to the same procedure asExample 21 to give the title compound (65 mg, Yield 23%).

¹H-NMR (500 HMz, CDCl₃); δ 11.04 (brs, 1H), 7.85 (s, 1H), 6.88 (m, 2H),6.61 (s, 1H), 6.36 (s, 1H), 6.13 (m, 1H), 6.00 (s, 1H), 4.71 (m, 1H),4.04 (m, 1H), 3.99 (s, 2H), 3.69 (m, 2H), 3.45 (m, 2H), 1.90 (m, 2H),1.55 (m, 4H), 1.32 (m, 2H)

Example 24 Synthesis of[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol

The compound (330 mg, 0.81 mmol) prepared in Preparation 29 and sodiummethanesulfinate instead of pyrazole were reacted according to the sameprocedure as Example 21 to give the title compound (152 mg, Yield 46%).

¹H-NMR (500 HMz, CDCl₃); δ 11.10 (brs, 1H), 7.01 (s, 1H), 6.88 (m, 1H),6.49 (s, 1H), 4.76 (m, 1H), 4.26 (s, 2H), 3.99 (m, 1H), 3.79 (m, 1H),3.68 (m, 1H), 3.43 (m, 2H), 2.73 (s, 3H), 1.96 (m, 2H), 1.57 (m, 4H),1.35 (m, 2H)

Preparation 30: Synthesis of 2,2-dimethyl-propionic acid(R)-2-{[5-(2,2-dimethyl-propionyloxymethyl)-7-nitro-1H-indole-2-carbonyl]-amino}-3-(4-methoxy-benzylsulfanyl)-propylester

The compound (3.1 g, 6.0 mmol) prepared in Preparation 28 was dissolvedin dichloromethane (50 ml). Triethylamine (1.2 g, 12.0 mmol) andpivaloyl chloride (0.8 g, 6.6 mmol) were added thereto, and the mixturewas stirred for 8 h at 0° C. After completion of the reaction, water wasadded, and the mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure and purified by column chromatography to give thetitle compound (3.6 g, Yield 98%).

¹H-NMR (400 HMz, CDCl₃); δ 10.47 (brs, 1H), 8.27 (s, 1H), 8.01 (s, 1H),7.27 (d, J=8.0 Hz, 2H), 6.92 (s, 1H), 6.83 (d, J=8.0 Hz, 2H), 6.76 (d,J=8.0 Hz, 1H), 5.25 (s, 2H), 4.56 (m, 1H), 4.42 (m, 1H), 4.22 (m, 1H),3.75 (s, 3H), 3.74 (s, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.25 (s, 9H),1.20 (s, 9H)

Preparation 31: Synthesis of 2,2-dimethyl-propionic acid(R)-2-[5-(2,2-dimethyl-propionyloxymethyl)-7-nitro-1H-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethylester

The compound (3.6 g, 5.9 mmol) prepared in Preparation 30 was reactedaccording to the same procedure as Step 3 of Preparation 19 to give thetitle compound (2.0 g, Yield 72%).

¹H-NMR (400 HMz, CDCl₃); δ 12.91 (brs, 1H), 8.35 (s, 1H), 7.96 (s, 1H),7.46 (s, 1H), 5.40 (m, 1H), 5.23 (s, 2H), 4.64 (m, 2H), 4.09 (m, 1H),3.64 (m, 1H), 1.27 (s, 9H), 1.19 (s, 9H)

Preparation 32: Synthesis of 2,2-dimethyl-propionic acid(R)-2-[7-amino-5-(2,2-dimethyl-propionyloxymethyl)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-ylmethylester

The compound (2.0 g, 4.2 mmol) prepared in Preparation 31 was reactedaccording to the same procedure as Step 4 of Preparation 19 to give thetitle compound (1.0 g, Yield 53%).

¹H-NMR (400 HMz, CDCl₃); δ 10.08 (brs, 1H), 7.26 (s, 1H), 6.87 (s, 1H),6.60 (s, 1H), 5.09 (s, 2H), 4.95 (m, 1H), 4.40 (m, 2H), 3.58 (m, 1H),3.35 (m, 1H), 1.20 (s, 9H), 1.12 (s, 9H)

Example 25 Synthesis of[7-cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-5-yl]-methanol

The compound (100 mg, 0.22 mmol) prepared in Preparation 34 was reactedaccording to the same procedures as Preparation 20 and Example 1 to givethe title compound (10 mg, Yield 13%).

¹H-NMR (400 HMz, CDCl₃); δ 9.63 (brs, 1H), 7.40 (s, 1H), 7.18 (s, 1H),6.90 (s, 1H), 4.80 (m, 1H), 4.73 (s, 2H), 4.06 (m, 1H), 3.84 (m, 1H),3.66 (m, 2H), 3.48 (m, 1H), 3.31 (m, 1H), 1.79 (m, 2H), 1.43 (m, 4H),1.26 (m, 2H)

Preparation 35: Synthesis of5-bromomethyl-7-nitro-indole-1,2-dicarboxylic acid 1-t-butyl ester2-ethyl ester

(Step 1)

4-Methyl-2-nitroaniline (20 g, 131 mmol) was reacted according to thesame procedures as Preparation 1 and Preparation 2 to give5-methyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester (16 g, Yield49%).

(Step 2)

The compound (15.1 g, 60.8 mmol) prepared in Step 1 was reactedaccording to the same procedures as Preparation 23 and Preparation 24 togive the title compound (6.3 g, Yield 24%).

Preparation 33: Synthesis of 5-chloro-7-nitro-1H-indole-2-carboxylicacid

The compound (15.0 g, 59.1 mmol) prepared in Preparation 5 was dissolvedin tetrahydrofuran (300 ml) and methanol (100 ml). Lithium hydroxidemonohydrate (7.43 g, 177 mmol) was dissolved in water (100 ml), andadded to the reaction solution, which was then stirred for 3 h at roomtemperature. After completion of the reaction, the reaction solution wasdistilled under reduced pressure to remove tetrahydrofuran and methanol.The residue was neutralized to about pH 6 using 3N hydrochloric acidsolution. The resulting solid was filtered and dried to give the titlecompound (13.1 g, Yield 92%).

Preparation 34: Synthesis of[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

(Step 1)

The compound (12.5 g, 52.0 mmol) prepared in Preparation 33 and thecompound (19.1 g, 62.4 mmol) prepared in Preparation 15 were dissolvedin N,N-dimethylformamide (200 ml). Triethylamine (8.7 ml, 62.4 mmol),HOBT (14.0 g, 104 mmol) and EDC (16.9 g, 88.4 mmol) were added thereto,and the mixture was stirred for 4 h at room temperature. Aftercompletion of the reaction, the reaction solution was concentrated,extracted with ethyl acetate, and washed using saturated sodiumbicarbonate solution and saturated aqueous ammonium chloride solution,respectively. The organic layer was concentrated and separated by columnchromatography to give(R)-3-[5-chloro-7-nitro-1H-indole-2-carbonyl)-amino]-4-(4-methoxy-benzylsulfanyl)-butyricacid methyl ester (20.2 g, 41.0 mmol, Yield 79%).

¹H-NMR (500 HMz, CDCl₃); δ 10.47 (br s, 1H), 8.24 (d, J=1.9 Hz, 1H),7.96 (d, J=1.9 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.89 (s, 1H), 6.81 (d,J=8.6 Hz, 2H), 4.58 (m, 1H), 3.75 (s, 3H), 3.73 (s, 2H), 3.71 (s, 3H),2.86 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.70 (m, 1H)

(Step 2)

The compound prepared in Step 1 was dissolved in dichloromethane (200ml). Phosphorus pentachloride (17.1 g, 82 mmol) was added thereto, andthe mixture was stirred for 1 h at room temperature. After completion ofthe reaction, the reaction solution was concentrated, and diethylether(200 ml) was added. The resulting solid was filtered and dried to give[(R)-2-(5-chloro-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester.

¹H-NMR (500 HMz, CDCl₃); δ 10.48 (br s, 1H), 8.22 (d, J=1.8 Hz, 1H),7.94 (d, J=1.8 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 6.96 (d, J=2.5 Hz, 1H),6.89 (d, J=8.6 Hz, 2H), 5.00 (m, 1H), 3.76 (s, 3H), 3.71 (m, 1H), 3.26(m, 1H), 2.99 (m, 1H), 2.67 (m, 1H)

(Step 3)

The compound prepared in Step 2 was dissolved in tetrahydrofuran (200ml), methanol (200 ml) and water (200 ml). Iron powder (22.9 g, 410mmol) and ammonium chloride (21.9 g, 410 mmol) were added thereto, andthe mixture was stirred for 1 h at 60° C. using a mechanical stirrer.After completion of the reaction, tetrahydrofuran (300 ml) was addedthereto. The mixture was filtered through a celite, washed withtetrahydrofuran (100 ml), distilled under reduced pressure, andconcentrated. The residue was extracted with ethyl acetate, washed withsaturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (9.0 g, Yield 68%).

Example 26 Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (4.9 g, 15.1 mmol) prepared in Preparation 34 was dissolvedin dichloroethane (100 ml). Cyclopentanone (2.7 ml, 30.3 mmol), aceticacid (0.86 ml, 15.1 mmol) and sodium triacetoxyborohydride (6.42 g, 30.3mmol) were added thereto, and the mixture was stirred for 36 h at roomtemperature. After completion of the reaction, the reaction solution waswashed with saturated aqueous sodium hydrogen carbonate solution (200ml), concentrated, and separated by column chromatography to give thetitle compound (5.15 g, Yield 87%).

¹H NMR (DMSO-d₆, ppm); δ 11.51 (s, 1H), 6.79 (s, 1H), 6.79 (s, 1H), 6.16(s, 1H), 6.13 (d, 1H), 4.85 (m, 1H), 3.80 (m, 1H), 3.62 (m, 1H), 3.58(s, 3H), 3.19 (m, 1H), 2.71 (m, 1H), 2.63 (m, 1H), 1.93 (m, 2H), 1.69(m, 2H), 1.56 (m, 4H)

FAB MS (m/e)=392

Example 27 Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (1.5 g, 3.83 mmol) prepared in Example 26 was dissolved intetrahydrofuran (100 ml) and methanol (50 ml). Lithium hydroxidemonohydrate (640 mg, 15.3 mmol) was dissolved in water (50 ml) and addedto the reaction solution, which was then stirred for 4 h at roomtemperature. After completion of the reaction, the reaction solution wasdistilled under reduced pressure to remove tetrahydrofuran and methanol.1N hydrochloric acid solution was added to the residue, and the mixturewas extracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure and separated by columnchromatography to give the title compound (13.1 g, Yield 92%).

¹H NMR (DMSO-d₆, ppm); δ 12.51 (br s, 1H), 11.51 (s, 1H), 6.79 (s, 1H),6.79 (s, 1H), 6.16 (s, 1H), 6.14 (d, 1H), 4.87 (m, 1H), 3.80 (m, 1H),3.61 (m, 1H), 3.19 (m, 1H), 2.72 (m, 1H), 2.64 (m, 1H), 1.93 (m, 2H),1.69 (m, 2H), 1.56 (m, 4H)

FAB MS (m/e)=378

Example 28 Synthesis of[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester

The compound (4.5 g, 18.7 mmol) prepared in Preparation 33 and thecompound (6.3 g, 19.7 mmol) prepared in Preparation 16 were reactedaccording to the same procedures as Preparation 34 and Example 26 togive the title compound (840 mg, Yield 11%).

¹H-NMR (500 HMz, CDCl₃); δ 10.01 (brs, 1H), 6.99 (s, 1H), 6.80 (s, 2H),6.43 (s, 1H), 5.03 (m, 1H), 4.07 (q, 2H), 3.81 (m, 1H), 3.64 (m, 1H),3.21 (m, 1H), 2.81 (m, 1H), 2.67 (m, 1H), 2.04 (m, 2H), 1.64 (m, 4H),1.49 (m, 2H), 1.20 (t, 3H)

Example 29 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-ethanol

The compound (550 mg, 1.4 mmol) prepared in Example 26 was dissolved intetrahydrofuran (50 ml). 1 M lithium borohydride tetrahydrofuransolution (2.11 ml, 2.11 mmol) was added thereto, and the mixture wasstirred for 1 h while raising the reaction temperature from −60° C. to0° C. After completion of the reaction, water was added. The mixture wasextracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and separated by columnchromatography to give the title compound (510 mg, Yield 100%).

¹H NMR (DMSO-d₆, ppm); δ 11.47 (1H, s), 6.79 (1H, s), 6.67 (1H, s), 6.11(1H, s), 6.09 (1H, m), 4.65 (1H, t), 4.54 (1H, m), 3.80 (2H, m), 3.61(2H, m), 3.52 (1H, m), 3.15 (1H, m), 2.47 (1H, m), 1.97 (2H, m), 1.68(2H, m), 1.54 (4H, m)

FAB MS (m/e)=364

Example 30 Synthesis of{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

The compound (1.0 g, 3.1 mmol) prepared in Preparation 34 was dissolvedin 1,2-dichloroethane (100 ml). Tetrahydro-4H-pyran-4-one (0.57 ml, 6.18mmol), sodium triacetoxyborohydride (1.31 g, 6.18 mmol) and acetic acid(0.18 ml, 3.09 mmol) were added thereto, and the mixture was stirred for24 h at room temperature. After completion of the reaction, the reactionsolution was diluted with dichloromethane, washed with saturated sodiumbicarbonate solution, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was distilled under reduced pressure, andpurified by column chromatography to give the title compound (0.5 g,Yield 40%).

¹H NMR (DMSO-d₆, ppm); δ 11.52 (1H, s), 6.81 (1H, s), 6.71 (1H, s), 6.28(1H, s), 6.07 (1H, d), 4.90 (1H, m), 3.86 (2H, m), 3.64 (3H, s), 3.62(2H, m), 3.44 (2H, t), 2.82-2.71 (2H, m), 1.94 (2H, m), 1.40 (2H, m)

FAB MS (m/e)=408

Example 31 Synthesis of{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (400 mg, 1.0 mmol) prepared in Example 30 was reactedaccording to the same procedure as Example 27 to give the title compound(360 mg, Yield 92%).

¹H NMR (DMSO-d₆, ppm); δ 12.43 (1H, s, br), 11.53 (1H, s), 6.81 (1H, s),6.71 (1H, s), 6.28 (1H, s), 6.06 (1H, d), 4.87 (1H, m), 3.87 (2H, m),3.62 (2H, m), 3.44 (2H, t), 3.19 (1H, m), 3.74 (1H, m), 2.63 (1H, m),1.94 (2H, m), 1.41 (2H, m)

FAB MS (m/e)=394

Example 32 Synthesis of2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

The compound (2.5 g, 6.12 mmol) prepared in Example 30 was reactedaccording to the same procedure as Example 29 to give the title compound(2.19 g, 5.76 mmol, Yield 94%).

¹H NMR (DMSO-d₆, ppm); δ 11.48 (1H, s), 6.81 (1H, s), 6.68 (1H, s), 6.28(1H, s), 6.05 (1H, d), 4.66 (1H, quin), 4.54 (1H, t), 3.87 (2H, m),3.61-3.54 (3H, m), 3.44 (2H, t), 3.15 (1H, m), 1.99-1.93 (3H, m), 1.73(1H, m), 1.40 (2H, m), 1.20 (1H, m)

FAB MS (m/e)=380

Preparation 35: Synthesis of[(R)-2-(7-amino-5-bromo-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

Methyl 5-bromo-7-nitro-1H-indole-2-carboxylate (2.7 g, 9.0 mmol)prepared in Preparation 6 was reacted according to the same proceduresas Preparation 33 and Preparation 34 to give the title compound (585 mg,Yield 18%).

Example 33 Synthesis of[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (340 mg, 0.9 mmol) prepared in Preparation 35 was reactedaccording to the same procedures as Example 26 and Example 27 to givethe title compound (250 mg, Yield 66%).

¹H-NMR (400 HMz, CDCl₃); δ 12.50 (br s, 1H), 7.10 (sm 1H), 7.06 (s, 1H),6.56 (s, 1H), 5.31 (m, 1H), 3.89 (m, 2H), 3.40 (m, 1H), 2.99 (m, 1H),2.83 (m, 1H), 2.08 (m, 2H), 1.86 (m, 2H), 1.66 (m, 4H)

Example 34 Synthesis of2-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-ethanol

(Step 1)

The compound (582 mg, 1.58 mmol) prepared in Preparation 35 was reactedaccording to the same procedure as Example 26 to give a cyclopentylaminecompound (430 mg, Yield 62%).

(Step 2)

The compound (150 mg, 0.34 mmol) prepared in Step 1 was dissolved intetrahydrofuran (8 ml). Lithium borohydride (15 mg, 0.69 mmol) was addedthereto, and the mixture was stirred for 1 h at room temperature. Aftercompletion of the reaction, water was added. The mixture was extractedwith ethyl acetate, washed with saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, and separated by column chromatographyto give the title compound (135 mg, Yield 96%).

¹H-NMR (400 HMz, CDCl₃); δ 10.42 (br s, 1H), 7.18 (s, 1H), 6.87 (s, 1H),6.59 (d, 1H), 4.67 (m, 2H), 4.02 (m, 2H), 3.91 (m, 1H), 3.63 (m, 1H),3.16 (t, 1H), 2.10 (m, 4H), 1.74 (m, 2H), 1.4 (m, 4H)

Example 35 Synthesis of{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (50 mg, 0.14 mmol) prepared in Preparation 44 was reactedaccording to the same procedures as Example 30 and Example 27 to givethe title compound (54 mg, Yield 88%).

¹H-NMR (400 HMz, CDCl₃); δ 7.07 (m, 2H), 6.50 (s, 1H), 5.10 (m, 1H),4.03 (m, 2H), 3.91 (m, 1H), 3.70-3.41 (m, 4H), 3.11 (m, 1H), 2.83 (m,2H), 2.52 (m, 1H), 2.04 (m, 2H), 1.69 (m, 2H)

Example 36 Synthesis of2-{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

The compound (50 mg, 0.14 mmol) prepared in Preparation 35 was reactedaccording to the same procedures as Example 30 and Step 2 of Example 34to give the title compound (35 mg, Yield 59%).

¹H-NMR (400 HMz, CDCl₃); δ 10.50 (br s, 1H), 7.19 (s, 1H), 6.89 (s, 1H),6.59 (d, 1H), 4.67 (m, 2H), 4.05 (m, 4H), 3.63 (m, 4H), 3.18 (t, 1H),2.12 (m, 4H), 1.64 (m, 4H)

Preparation 36: Synthesis of[(R)-2-(7-amino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

Ethyl 5-fluoro-7-nitro-1H-indole-2-carboxylate (2.3 g, 9.1 mmol)prepared in Preparation 2 was reacted according to the same proceduresas Preparation 33 and Preparation 34 to give the title compound (650 mg,Yield 23%).

Example 37 Synthesis of[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (361 mg, 1.2 mmol) prepared in Preparation 36 was reactedaccording to the same procedures as Example 26 and Example 27 to givethe title compound (189 mg, Yield 44%).

¹H-NMR (400 HMz, CDCl₃); δ 11.09 (br s, 1H), 6.73 (s, 1H), 6.45 (dd,1H), 6.07 (dd, 1H), 4.98 (m, 1H), 3.79 (m, 1H), 3.59 (m, 1H), 3.16 (m,1H), 2.79 (m, 1H), 2.60 (m, 1H), 1.96 (m, 2H), 1.71 (m, 2H), 1.58 (m,4H)

Example 38 Synthesis of[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester

The compound (80 mg, 0.22 mmol) prepared in Example 37 was dissolved inethanol (2 ml). Acetyl chloride (0.1 ml) was added thereto, and themixture was stirred for 8 h at room temperature. After completion of thereaction, the reaction solution was diluted with ethyl acetate, washedwith saturated sodium bicarbonate solution, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was distilled underreduced pressure, and purified by column chromatography to give thetitle compound (50 mg, Yield 58%).

¹H-NMR (400 HMz, CDCl₃); δ 10.71 (br s, 1H), 6.86 (s, 1H), 6.64 (dd,1H), 6.23 (dd, 1H), 5.07 (m, 1H), 3.99 (q, 2H), 3.91 (m, 1H), 3.76 (m,1H), 3.64 (m, 1H), 3.22 (m, 1H), 2.88 (m, 1H), 2.65 (m, 1H), 2.00 (m,2H), 1.63 (m, 4H), 1.40 (m, 2H), 1.12 (t, 3H)

Example 39 Synthesis of2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol

The compound (90 mg, 0.29 mmol) prepared in Preparation 36 was reactedaccording to the same procedures as Example 26 and Step 2 of Example 34to give the title compound (46 mg, Yield 46%).

¹H-NMR (400 HMz, CDCl₃); δ 10.90 (br s, 1H), 6.91 (s, 1H), 6.65 (dd,1H), 6.26 (dd, 1H), 4.68 (m, 1H), 4.08 (m, 2H), 3.88 (m, 1H), 3.62 (m,1H), 3.15 (t, 1H), 2.10 (m, 4H), 1.74 (m, 2H), 1.62 (m, 4H)

Example 40 Synthesis of{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (852 mg, 2.8 mmol) prepared in Preparation 36 was reactedaccording to the same procedures as Example 30 and Example 27 to givethe title compound (970 mg, Yield 92%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.45 (s, 1H), 6.75 (d, 1H), 6.22 (dd, 1H),6.16 (d, J=6.8 Hz, 1H), 4.91 (m, 1H), 3.88 (m, 2H), 3.66 (m, 1H), 3.61(m, 1H), 3.48 (m, 2H), 3.22 (m, 1H), 2.80 (m, 1H), 2.65 (m, 1H), 2.99(m, 2H), 1.40 (m, 2H)

Example 41 Synthesis of2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

The compound (1.24 g, 4.0 mmol) prepared in Preparation 36 was reactedaccording to the same procedures as Example 30 and Step 2 of Example 34to give the title compound (810 mg, Yield 55%).

¹H-NMR (400 HMz, CDCl₃); δ 10.69 (br s, 1H), 6.87 (s, 1H), 6.63 (d, 1H),6.22 (d, 1H), 4.87 (m, 1H), 4.66 (m, 1H), 4.02 (m, 4H), 3.55 (m, 4H),3.15 (m, 1H), 2.04 (m, 4H), 1.54 (m, 2H)

Preparation 37: Synthesis of[(R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acidmethyl ester

Methyl 7-nitro-1H-indole-2-carboxylate (14.0 g, 63.6 mmol) prepared inPreparation 8 was reacted according to the same procedures asPreparation 33 and Preparation 34 to give the title compound (6.5 g,Yield 35%).

Example 42 Synthesis of[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

(Step 1)

The compound (5.0 g, 17.3 mmol) prepared in Preparation 37 was reactedaccording to the same procedure as Example 26 to give a methyl estercompound.

(Step 2)

The compound prepared in Step 1 was reacted according to the sameprocedure as Example 27 to give the title compound (5.44 g, 2 steps,Yield 91%).

¹H-NMR (400 HMz, CDCl₃); δ 11.77 (br s, 1H), 7.04 (d, 1H), 6.97 (m, 2H),6.43 (d, 1H), 5.34 (m, 1H), 3.88 (m, 1H), 3.69 (m, 1H), 3.19 (m, 1H),2.72 (m, 1H), 2.60 (m, 1H), 2.01 (m, 2H), 1.74 (m, 2H), 1.59 (m, 4H)

Example 43 Synthesis of[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester

The compound (500 mg, 1.46 mmol) prepared in Example 42 was reactedaccording to the same procedure as Example 38 to give the title compound(420 mg, Yield 78%).

¹H-NMR (400 HMz, CDCl₃); δ 10.12 (br s, 1H), 7.05 (m, 1H), 6.99 (m, 1H),6.91 (d, 1H), 6.51 (d, 1H), 5.07 (m, 1H), 4.09 (q, 2H), 3.87 (m, 1H),3.65 (m, 1H), 3.21 (m, 1H), 2.86 (m, 1H), 2.65 (m, 1H), 2.01 (m, 2H),1.74 (m, 2H), 1.62 (m, 4H), 1.46 (m, 2H), 1.81 (t, 3H)

Example 44 Synthesis of2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol

The compound (1.46 g, 5.06 mmol) prepared in Preparation 37 was reactedaccording to the same procedures as Example 26 and Step 2 of Example 34to give the title compound (1.44 g, Yield 78%).

¹H NMR (DMSO-d₆, ppm); δ 11.28 (1H, s), 6.77-6.74 (2H, m), 6.69 (1H, s),6.25 (1H, d), 5.78 (1H, d), 4.65 (1H, quin), 4.53 (1H, t), 3.82 (1H, m),3.60 (2H, m), 3.51 (1H, m), 3.11 (1H, m), 1.99-1.91 (3H, m), 1.75-1.67(3H, m), 1.56-1.54 (4H, m)

FAB MS (m/e)=330

Example 45 Synthesis of{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (1.32 g, 4.58 mmol) prepared in Preparation 37 was reactedaccording to the same procedures as Example 30 and Example 27 to givethe title compound (1.25 g, Yield 76%).

¹H NMR (DMSO-d₆, ppm); δ 12.42 (1H, s, br), 11.34 (1H, s), 6.80 (1H, d),6.72 (1H, s), 6.33 (1H, d), 5.79 (1H, d), 4.86 (1H, quin), 3.88 (2H, m),3.60-3.52 (2H, m), 3.42 (2H, t), 3.17 (1H, m), 2.74 (1H, m), 2.59 (1H,m), 1.94 (2H, m), 1.39 (2H, m)

FAB MS (m/e)=360

Example 46 Synthesis of2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

The compound (529 mg, 1.83 mmol) prepared in Preparation 37 was reactedaccording to the same procedures as Example 30 and Step 1 of Example 34to give the title compound (340 mg, Yield 54%).

¹H NMR (DMSO-d₆, ppm); δ 11.29 (1H, s), 6.79 (2H, m), 6.70 (1H, s), 6.33(1H, d), 5.76 (1H, d), 4.66 (1H, quin), 4.54 (1H, t), 3.88 (2H, m),3.62-3.59 (3H, m), 3.53 (1H, t), 3.43 (2H, m), 3.12 (1H, m), 1.96 (3H,m), 1.75 (1H, m), 1.40 (2H, m)

FAB MS (m/e)=346

Preparation 38: Synthesis of[(R)-2-(7-amino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

Methyl 5-methoxy-7-nitro-1H-indole-2-carboxylate (2.5 g, 6.0 mmol)prepared in Preparation 9 was reacted according to the same proceduresas Preparation 33 and Preparation 34 to give the title compound (1.0 g,Yield 52%).

Example 47 Synthesis of[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (1.0 g, 3.13 mmol) prepared in Preparation 38 was reactedaccording to the same procedure as Example 26 to give the title compound(490 g, Yield 40%).

¹H NMR (DMSO-d₆, ppm); δ 11.24 (1H, s), 6.62 (1H, s), 6.22 (1H, s), 5.89(1H, d), 5.84 (1H, s), 4.83 (1H, quin), 3.77 (1H, m), 3.64 (3H, s), 3.59(3H, s), 3.56 (1H, m), 3.15 (1H, m), 2.69 (1H, m), 2.58 (1H, m), 1.90(2H, m), 1.67 (2H, m), 1.51 (4H, m)

FAB MS (m/e)=388

Example 48 Synthesis of[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (300 mg, 0.78 mmol) prepared in Example 47 was reactedaccording to the same procedure as Example 27 to give the title compound(240 mg, Yield 82%).

¹H NMR (DMSO-d₆, ppm); δ 12.54 (1H, s, br), 11.21 (1H, s), 6.63 (1H, s),6.23 (1H, s), 5.89 (1H, d), 5.84 (1H, s), 4.84 (1H, quin), 3.77 (1H, m),3.64 (3H, s), 3.56 (1H, m), 3.15 (1H, m), 2.69 (1H, m), 2.58 (1H, m),1.90 (2H, m), 1.67 (2H, m), 1.52 (4H, m)

FAB MS (m/e)=374

Example 49 Synthesis of[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester

The compound (200 mg, 0.54 mmol) prepared in Example 48 was reactedaccording to the same procedure as Example 38 to give the title compound(124 mg, Yield 57%).

¹H-NMR (400 HMz, CDCl₃); δ 10.73 (br s, 1H), 6.83 (s, 1H), 6.43 (s, 1H),6.16 (s, 1H), 5.07 (m, 1H), 4.00-3.88 (m, 3H), 3.80 (s, 3H), 3.76 (m,1H), 3.62 (m, 1H), 3.20 (m, 1H), 2.83 (m, 1H), 2.63 (m, 1H), 1.98 (m,2H), 1.61 (m, 4H), 1.40 (m, 2H), 1.12 (t, 3H)

Example 50 Synthesis of{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

The compound (4.8 g, 14.8 mmol) prepared in Preparation 38 was reactedaccording to the same procedure as Example 30 to give the title compound(2.5 g, Yield 42%).

Example 51 Synthesis of{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (30 mg, 0.07 mmol) prepared in Example 50 was reactedaccording to the same procedure as Example 27 to give the title compound(8.7 g, Yield 30%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.21 (br s, 1H), 6.64 (m, 1H), 6.26 (m,1H), 5.95 (m, 1H), 5.84 (m, 1H), 4.85 (m, 1H), 3.85 (m, 1H), 3.64 (s,3H), 3.63-3.49 (m, 2H), 3.43 (m, 2H), 3.17 (m, 1H), 2.73 (m, 1H), 2.62(m, 1H), 1.94 (m, 2H), 1.72 (m, 1H), 1.38 (m, 2H)

Example 52 Synthesis of[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

Methyl 5-ethoxy-7-nitro-1H-indole-2-carboxylate (1.5 g, 5.7 mmol)prepared in Preparation 11 was reacted according to the same proceduresas Preparation 33, Preparation 34, Example 26 and Example 27 in theorder to give the title compound (150 mg, Yield 7%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.24 (br s, 1H), 6.65 (d, J=2.0 Hz, 1H),6.26 (d, J=2.0 Hz, 1H), 5.92 (d, J=6.0 Hz, 1H), 5.88 (d, J=2.0 Hz, 1H),4.89 (m, 1H), 3.94 (q, 2H), 3.81 (m, 1H), 3.65 (m, 1H), 3.20 (m, 1H),2.74 (m, 1H), 2.62 (m, 1H), 1.94 (m, 2H), 1.72 (m, 2H), 1.61 (m, 4H),1.31 (t, 3H)

Preparation 39: Synthesis of 7-nitro-5-propoxy-1H-indole-2-carboxylicacid ethyl ester

2-Nitro-4-propoxy-phenylamine (20 g, 102 mmol) was reacted according tothe same procedures as Preparation 1 and Preparation 2 to give the titlecompound (1.5 g, Yield 5%).

Example 53 Synthesis of[(R)-2-(7-cyclopentylamino-5-propoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

Ethyl 5-propoxy-7-nitro-1H-indole-2-carboxylate (1.4 g, 4.82 mmol)prepared in Preparation 39 was reacted according to the same proceduresas Preparation 33, Preparation 34, Example 26 and Example 27 in theorder to give the title compound (70 mg, Yield 4%).

¹H-NMR (500 HMz, CDCl₃); δ 12.79 (br s, 1H), 7.05 (s, 1H), 6.26 (s, 1H),6.22 (s, 1H), 5.14 (br s, 1H), 3.88 (m, 3H), 3.41 (m, 2H), 3.07 (m, 1H),2.83 (m, 1H), 2.03 (m, 2H), 1.82 (m, 3H), 1.69 (m, 2H), 1.60 (m, 2H),1.04 (t, 3H)

Preparation 40: Synthesis of[(R)-2-(7-amino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

Methyl 5-phenoxy-7-nitro-1H-indole-2-carboxylate (550 mg, 1.84 mmol)prepared in Preparation 12 was reacted according to the same proceduresas Preparation 33 and Preparation 34 to give the title compound (150 mg,Yield 16%).

Example 54 Synthesis of[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (65 mg, 0.13 mmol) prepared in Preparation 40 was reactedaccording to the same procedures as Example 26 and Example 27 to givethe title compound (20 mg, Yield 35%).

¹H-NMR (400 HMz, CDCl₃); δ 11.92 (br s, 1H), 7.28 (m, 2H), 7.00 (m, 4H),6.56 (s, 1H), 6.22 (s, 1H), 5.34 (br s, 1H), 3.81 (br s, 1H), 3.70 (m,1H), 3.22 (d, J=12.0 Hz, 1H), 2.76-2.62 (m, 2H), 1.96 (m, 2H), 1.73 (m,2H), 1.58 (m, 4H)

Example 55 Synthesis of{(R)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (65 mg, 0.13 mmol) prepared in Preparation 40 was reactedaccording to the same procedures as Example 30 and Example 27 to givethe title compound (13 mg, Yield 22%).

¹H-NMR (400 HMz, CDCl₃); δ 11.98 (br s, 1H), 7.28 (m, 2H), 7.00 (m, 4H),6.58 (s, 1H), 6.22 (s, 1H), 5.34 (br s, 1H), 3.98 (br s, 2H), 3.70 (m,1H), 3.50 (m, 3H), 3.21 (m, 2H), 2.74 (m, 1H), 2.66 (m, 1H), 2.05 (m,2H), 1.58 (m, 2H)

Preparation 41: Synthesis of{(R)-2-[7-amino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

7-Nitro-5-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid ethyl ester (1.0g, 3.1 mmol) prepared in Preparation 13 was reacted according to thesame procedures as Preparation 33 and Preparation 34 to give the titlecompound (160 mg, Yield 14%).

Example 56 Synthesis of{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

The compound (80 mg, 0.21 mmol) prepared in Preparation 41 was reactedaccording to the same procedure as Example 26 to give the title compound(45 mg, Yield 48%).

¹H-NMR (400 HMz, CDCl₃); δ 10.89 (br s, 1H), 8.41 (d, 1H), 8.26 (m, 1H),7.27 (m, 1H), 7.19 (m, 1H), 6.85 (s, 1H), 6.62 (d, 1H), 6.22 (m, 1H),5.04 (m, 1H), 4.13 (br s, 1H), 3.78 (m, 1H), 3.65 (m, 1H), 3.59 (s, 3H),3.20 (m, 1H), 2.83 (m, 1H), 2.67 (m, 1H), 1.98 (m, 2H), 1.61 (m, 4H),1.46 (m, 2H)

Example 57 Synthesis of{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (35 mg, 0.08 mmol) prepared in Example 56 was reactedaccording to the same procedure as Example 27 to give the title compound(15 mg, Yield 44%).

¹H-NMR (400 HMz, CDCl₃); δ 11.86 (br s, 1H), 8.40 (d, 1H), 8.26 (m, 1H),7.25 (m, 1H), 7.17 (m, 1H), 6.96 (s, 1H), 6.57 (d, 1H), 6.18 (d, 1H),5.33 (br s, 1H), 3.80 (br s, 1H), 3.70 (m, 1H), 3.21 (m, 1H), 2.73 (m,1H), 2.65 (m, 1H), 1.96 (m, 2H), 1.72 (m, 2H), 1.58 (m, 4H)

Example 58 Synthesis of{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

The compound (480 g, 0.21 mmol) prepared in Preparation 41 was reactedaccording to the same procedure as Example 30 to give the title compound(35 mg, Yield 36%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 8.30 (d, 1H), 8.25 (m,1H), 7.34 (m, 1H), 7.29 (m, 1H), 6.76 (d, 1H), 6.46 (d, 1H), 6.18 (d,1H), 4.93 (m, 1H), 3.87 (m, 3H), 3.66 (s, 3H), 3.59 (m, 1H), 3.44 (m,2H), 3.23 (m, 1H), 2.81 (m, 2H), 1.95 (m, 2H), 1.43 (m, 2H)

Example 59 Synthesis of{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (25 mg, 0.05 mmol) prepared in Example 58 was reactedaccording to the same procedure as Example 27 to give the title compound(15 mg, Yield 58%).

¹H-NMR (400 HMz, MeOH-d₄); δ 8.14 (s, 1H), 8.07 (s, 1H), 7.25 (m, 2H),6.76 (s, 1H), 6.45 (s, 1H), 6.12 (d, 1H), 4.84 (m, 1H), 3.85 (m, 1H),3.83 (m, 1H), 3.53 (m, 1H), 3.40 (m, 2H), 3.21 (m, 2H), 3.12 (m, 1H),2.73 (m, 1H), 2.59 (m, 1H), 1.93 (m, 2H), 1.46 (m, 2H)

Preparation 42: Synthesis of[(R)-2-(7-amino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

Methyl 5-methyl-7-nitro-1H-indole-2-carboxylate (3.4 g, 14.5 mmol)prepared in Preparation 7 was reacted according to the same proceduresas Preparation 33 and Preparation 34 to give the title compound (1.7 g,Yield 39%).

Example 60 Synthesis of[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (1.7 g, 5.67 mmol) prepared in Preparation 42 was reactedaccording to the same procedure as Example 26 to give the title compound(1.2 g, Yield 58%).

¹H NMR (DMSO-d₆, ppm); δ 11.19 (1H, s), 6.62 (1H, s), 6.55 (1H, s), 6.07(1H, s), 5.75 (1H, d), 4.88 (1H, quin), 3.79 (1H, m), 3.63-3.57 (5H, m),3.17 (1H, m), 2.82-2.73 (2H, m), 2.23 (3H, s), 1.94 (2H, m), 1.68 (2H,m), 1.55 (3H, m)

FAB MS (m/e)=372

Example 61 Synthesis of[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (12 mg, 0.03 mmol) prepared in Example 60 was reactedaccording to the same procedure as Example 27 to give the title compound(5 mg, Yield 43%).

¹H NMR (DMSO-d₆, ppm); δ 12.42 (1H, s, br), 11.21 (1H, s), 6.61 (1H, s),6.54 (1H, s), 6.02 (1H, s), 5.76 (1H, d), 4.87 (1H, quin), 3.77 (1H, m),3.62 (2H, t), 3.16 (1H, m), 2.81-2.72 (2H, m), 2.23 (3H, s), 1.94 (2H,m), 1.68 (2H, m), 1.55 (3H, m)

FAB MS (m/e)=358

Example 62 Synthesis of{(R)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (55 mg, 0.18 mmol) prepared in Preparation 42 was reactedaccording to the same procedures as Example 30 and Example 27 to givethe title compound (47 mg, Yield 70%).

¹H-NMR (500 HMz, CDCl₃); δ 11.85 (br s, 1H), 6.97 (d, 1H), 6.76 (s, 1H),6.26 (s, 1H), 5.32 (m, 1H), 3.99 (m, 2H), 3.71 (m, 1H), 3.65 (m, 1H),3.54 (m, 2H), 3.23 (m, 1H), 2.76 (m, 1H), 2.64 (m, 1H), 2.31 (s, 3H),2.06 (m, 2H), 1.58 (m, 2H)

Preparation 43: Synthesis of{(R)-2-[7-(1,4-dioxa-spiro[4,5]dec-8-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

The compound (98 mg, 0.32 mmol) prepared in Preparation 42 and1,4-cyclohexandione monoethylene acetal instead of cyclopentanone werereacted according to the same procedure as Example 26 to give the titlecompound (31 mg, Yield 23%).

¹H-NMR (500 HMz, CDCl₃); δ 10.62 (br s, 1H), 6.85 (s, 1H), 6.77 (s, 1H),6.31 (s, 1H), 4.98 (m, 1H), 3.96 (m, 4H), 3.72 (s, 3H), 3.64 (m, 1H),3.55 (m, 1H), 3.21 (m, 1H), 2.89 (m, 1H), 2.66 (m, 1H), 2.37 (s, 3H),2.08 (m, 2H), 1.99 (m, 2H), 1.69 (m, 4H)

Example 63 Synthesis of{(R)-2-[5-methyl-7-(4-oxo-cyclohexylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (40 mg, 0.09 mmol) prepared in Preparation 43 was dissolvedin tetrahydrofuran (2 ml), methanol (2 ml) and water (2 ml). Lithiumhydroxide monohydrate (8 mg, 0.18 mmol) was added thereto, and themixture was stirred for 4 h at room temperature. After completion of thereaction, 1N hydrochloric acid solution was added. The mixture wasextracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography.

Thus purified compound was dissolved in acetone (5 ml).p-Toluenesulfonic acid (5 mg) was added thereto, and the mixture wasstirred for 8 h at room temperature. After completion of the reaction,water was added. The mixture was extracted with ethyl acetate, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and separated by column chromatography to give the titlecompound (7 mg, Yield 20%).

¹H-NMR (500 HMz, CDCl₃); δ 11.99 (br s, 1H), 7.00 (s, 1H), 6.79 (s, 1H),6.30 (s, 1H), 5.34 (m, 1H), 3.89 (m, 1H), 3.71 (m, 1H), 3.21 (m, 1H),2.66 (m, 2H), 2.59 (m, 2H), 2.43-2.35 (m, 5H), 2.26 (m, 2H), 1.97 (m,2H)

Preparation 44: Synthesis of{(R)-2-[7-amino-5-(4-methanesulfonyl-phenoxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester

The compound (900 mg, 2.30 mmol) prepared in Preparation 14 was reactedaccording to the same procedures as Preparation 33 and Preparation 34 togive the title compound (328 mg, Yield 31%).

Example 64 Synthesis of{(R)-2-[7-cyclopentylamino-5-(4-methanesulfonyl-phenoxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid

The compound (320 mg, 0.7 mmol) prepared in Preparation 44 was reactedaccording to the same procedures as Example 26 and Example 27 to givethe title compound (45 mg, Yield 13%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.71 (br s, 1H), 7.81 (d, 2H), 7.05 (m,2H), 6.65 (s, 1H), 6.49 (s, 1H), 6.35 (m, 1H), 5.96 (s, 1H), 4.86 (m,1H), 3.75 (m, 1H), 3.52 (m, 1H), 3.17 (m, 1H), 3.12 (s, 3H), 1.87 (m,2H), 1.67 (m, 2H), 1.53 (m, 4H)

Preparation 45: Synthesis of(R)-3-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)-amino]-4-(4-methoxy-benzylsulfanyl)-butyricacid methyl ester

The compound (12.9 g, 54.8 mmol) prepared in Preparation 27 was reactedaccording to the same procedure as Step 1 of Preparation 34 to give thetitle compound (15.3 g, Yield 57%).

¹H-NMR (500 HMz, CDCl₃); δ 10.43 (br s, 1H), 8.28 (s, 1H), 8.00 (s, 1H),7.25 (m, 2H), 6.92 (d, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 4.86 (m, 2H),4.59 (m, 1H), 3.76 (s, 3H), 3.73 (s, 2H), 3.69 (s, 3H), 2.88 (m, 1H),2.82 (m, 2H), 2.73 (m, 1H), 2.69 (m, 1H)

Preparation 46: Synthesis of[(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (4.8 g, 0.8 mmol) prepared in Preparation 45 was reactedaccording to the same procedure as Preparation 29 to give the titlecompound (3.2 g, Yield 88%).

¹H-NMR (500 HMz, CDCl₃); δ 12.82 (br s, 1H), 8.43 (s, 1H), 8.04 (s, 1H),7.49 (s, 1H), 5.25 (m, 1H), 4.74 (s, 2H), 4.03 (m, 1H), 3.57 (m, 1H),3.45 (m, 1H), 2.99 (m, 1H)

Preparation 47: Synthesis of[(R)-2-(7-nitro-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (500 mg, 1.4 mmol) prepared in Preparation 46 was dissolvedin N,N-dimethylformamide (10 ml). Potassium hydride (82 mg, 2.0 mmol)and phenol (192 mg, 2.0 mmol) were added thereto, and the mixture wasstirred for 8 h at 0° C.˜room temperature. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure to give the title compound (55 mg,Yield 6%).

¹H-NMR (500 HMz, CDCl₃); δ 10.46 (br s, 1H), 8.34 (s, 1H), 8.06 (s, 1H),7.31 (m, 2H), 7.25 (s, 1H), 7.00 (m, 3H), 5.19 (s, 2H), 5.06 (m, 1H),3.77 (s, 3H), 3.71 (m, 1H), 3.26 (m, 1H), 2.97 (m, 1H), 2.69 (m, 1H)

Example 65 Synthesis of[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (33 mg, 0.08 mmol) prepared in Preparation 47 was reactedaccording to the same procedures as Step 3 of Preparation 34 and Example26 to give the title compound (16 mg, Yield 43%).

¹H-NMR (500 HMz, CDCl₃); δ 9.49 (br s, 1H), 7.27 (m, 2H), 7.10 (s, 1H),7.01 (m, 2H), 6.93 (m, 1H), 6.89 (s, 1H), 6.59 (s, 1H), 5.07 (s, 2H),5.02 (m, 1H), 3.93 (m, 1H), 3.71 (s, 3H), 3.65 (m, 1H), 3.21 (m, 1H),2.88 (m, 1H), 2.68 (m, 1H), 2.04 (m, 2H), 1.75 (m, 2H), 1.58 (m, 4H)

Example 66 Synthesis of[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (11 mg, 0.02 mmol) prepared in Example 65 was reactedaccording to the same procedure as Example 27 to give the title compound(5 mg, Yield 45%).

¹H-NMR (500 HMz, CDCl₃); δ 11.79 (br s, 1H), 7.26 (m, 2H), 7.02 (m, 2H),6.99 (s, 1H), 6.92 (m, 1H), 6.48 (s, 1H), 5.35 (m, 1H), 5.07 (s, 2H),3.89 (m, 1H), 3.71 (m, 1H), 3.21 (m, 1H), 2.75 (m, 1H), 2.63 (m, 1H),2.00 (m, 2H), 1.73 (m, 2H), 1.59 (m, 4H), 1.75 (m, 2H)

Preparation 48: Synthesis of[(R)-2-(7-nitro-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (87 mg, 0.24 mmol) prepared in Preparation 46 andpyrrolidine instead of dimethylamine were reacted according to the sameprocedure as Example 15 to give the title compound (56 mg, Yield 58%).

¹H-NMR (500 HMz, CDCl₃); δ 8.28 (s, 1H), 8.26 (s, 1H), 7.00 (s, 1H),5.03 (m, 1H), 4.10 (s, 2H), 3.74 (s, 3H), 3.68 (m, 1H), 2.94 (m, 1H),2.92 (m, 4H), 2.66 (m, 1H), 1.98 (m, 4H)

Example 67 Synthesis of[(R)-2-(7-cyclopentylamino-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (56 mg, 0.14 mmol) prepared in Preparation 48 was reactedaccording to the same procedures as Step 3 of Preparation 34 and Example26 to give the title compound (13 mg, Yield 21%).

¹H-NMR (400 HMz, CDCl₃); δ 10.20 (br s, 1H), 6.97 (s, 1H), 6.88 (s, 1H),6.73 (s, 1H), 5.01 (m, 1H), 4.04 (s, 2H), 4.02 (m, 1H), 3.73 (s, 3H),3.65 (m, 1H), 3.22 (m, 1H), 3.10 (m, 4H), 2.87 (m, 1H), 2.68 (m, 1H),2.06 (m, 3H), 1.95 (m, 4H), 1.65 (m, 3H), 1.47 (m, 2H)

Preparation 49: Synthesis of[(R)-2-(5-methanesulfonylmethyl-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (110 mg, 0.30 mmol) prepared in Preparation 55 and sodiummethanesulfinate instead of dimethylamine were reacted according to thesame procedure as Example 15 to give the title compound (92 mg, Yield74%).

¹H-NMR (500 HMz, CDCl₃); δ 10.55 (br s, 1H), 8.26 (s, 1H), 8.08 (s, 1H),7.04 (s, 1H), 5.06 (m, 1H), 4.40 (s, 2H), 3.77 (s, 3H), 3.48 (m, 1H),3.27 (m, 1H), 2.99 (m, 1H), 2.86 (s, 3H), 2.71 (m, 1H)

Example 68 Synthesis of[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester

The compound (92 mg, 0.22 mmol) prepared in Preparation 49 was reactedaccording to the same procedures as Step 3 of Preparation 34 and Example26 to give the title compound (31 mg, Yield 31%).

¹H-NMR (500 HMz, CDCl₃); δ 10.22 (br s, 1H), 7.00 (s, 1H), 6.87 (s, 1H),6.50 (s, 1H), 5.05 (m, 1H), 4.27 (s, 2H), 3.87 (m, 1H), 3.61 (s, 3H),3.22 (m, 1H), 2.83 (m, 1H), 2.72 (s, 3H), 2.66 (m, 1H), 2.03 (m, 2H),1.64 (m, 4H), 1.46 (m, 2H)

Example 69 Synthesis of[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid

The compound (29 mg, 0.07 mmol) prepared in Example 68 was reactedaccording to the same procedure as Example 27 to give the title compound(19 mg, Yield 67%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.68 (br s, 1H), 6.85 (s, 1H), 6.71 (s,1H), 6.33 (s, 1H), 6.18 (m, 1H), 4.88 (m, 1H), 4.35 (s, 2H), 3.84 (m,1H), 3.56 (m, 1H), 3.20 (m, 1H), 2.84 (s, 3H), 2.55 (m, 1H), 2.09 (m,1H), 1.97 (m, 2H), 1.73 (m, 2H), 1.58 (m, 4H)

Example 70 Synthesis of2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol

The compound (720 mg, 1.60 mmol) prepared in Example 68 was dissolved intetrahydrofuran (20 ml). 2 M lithium borohydride tetrahydrofuransolution (1.6 ml, 3.2 mmol) was added thereto, and the mixture wasstirred for 3 h at room temperature. After completion of the reaction,water was added. The mixture was extracted with ethyl acetate, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and separated by column chromatography to give the titlecompound (292 mg, Yield 43%).

¹H-NMR (500 HMz, CDCl₃); δ 10.41 (br s, 1H), 6.98 (s, 1H), 6.90 (s, 1H),6.49 (s, 1H), 4.68 (m, 1H), 4.28 (s, 2H), 3.96 (m, 3H), 3.59 (m, 1H),3.13 (m, 1H), 2.05 (m, 4H), 1.72 (m, 2H), 1.60 (m, 4H)

Preparation 50: Synthesis ofcyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methanesulfonylmethyl-1H-indol-7-yl}-amine

The compound (178 mg, 0.42 mmol) prepared in Example 70 was dissolved intetrahydrofuran (10 ml). Iodine (161 mg, 0.63 mmol), triphenylphosphine(166 mg, 0.63 mmol) and imidazole (86 mg, 1.23 mmol) were added thereto,and the mixture was stirred for 8 h at room temperature. Aftercompletion of the reaction, water was added. The mixture was extractedwith ethyl acetate, washed with saturated sodium chloride solution,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, and separated by column chromatographyto give the title compound (120 mg, Yield 54%).

Example 71 Synthesis ofcyclopentyl-{5-methanesulfonylmethyl-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (116 mg, 0.22 mmol) prepared in Preparation 50 wasdissolved in N,N-dimethylformamide (4 ml). Morpholine (57 mg, 0.66 mmol)was added thereto, and the mixture was stirred for 8 h at roomtemperature. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reduced pressureto give the title compound (68 mg, Yield 64%).

¹H-NMR (500 HMz, CDCl₃); δ 10.60 (br s, 1H), 6.99 (s, 1H), 6.89 (s, 1H),6.49 (s, 1H), 4.79 (m, 1H), 4.26 (s, 2H), 3.86 (m, 1H), 3.57 (m, 5H),3.19 (m, 1H), 2.72 (s, 3H), 2.45 (m, 2H), 2.32 (m, 2H), 2.26 (m, 2H),2.04 (m, 2H), 1.80 (m, 2H), 1.66 (m, 4H), 1.41 (m, 2H)

Example 72 Synthesis of1-(4-{2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone

The compound (129 mg, 0.24 mmol) prepared in Preparation 50 and1-acetylpiperazine instead of morpholine were reacted according to thesame procedure as Example 71 to give the title compound (54 mg, Yield42%).

¹H-NMR (500 HMz, CDCl₃); δ 10.62 (br s, 1H), 6.99 (s, 1H), 6.89 (s, 1H),6.46 (s, 1H), 4.77 (m, 1H), 4.26 (s, 2H), 3.87 (m, 1H), 3.57 (m, 1H),3.30 (m, 2H), 3.16 (m, 1H), 2.72 (s, 3H), 2.46 (m, 2H), 2.31 (m, 2H),2.21 (m, 2H), 2.04 (s, 3H), 2.03 (m, 2H), 1.79 (m, 2H), 1.64 (m, 4H),1.45 (m, 2H)

Example 73 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone

The compound (50 mg, 0.13 mmol) prepared in Example 27 was dissolved inN,N-dimethylformamide (2 ml). Morpholine (17 mg, 0.20 mmol), EDC (43 mg,0.23 mmol) and HOBT (36 mg, 0.26 mmol) were added thereto, and themixture was stirred for 8 h at room temperature. After completion of thereaction, saturated sodium bicarbonate solution was added. The mixturewas extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and concentrated. The residue was purified by columnchromatography to give the title compound (22 mg, Yield 37%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.52 (br s, 1H), 6.80 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.95 (m, 1H), 3.81 (m, 1H), 3.63 (m,1H), 3.41 (m, 8H), 3.12 (m, 1H), 2.85 (m, 1H), 2.69 (m, 1H), 1.93 (m,2H), 1.68 (m, 2H), 1.56 (m, 4H)

Example 74 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide

The compound (50 mg, 0.13 mmol) prepared in Example 27 and4-(2-aminoethyl)morpholine instead of morpholine were reacted accordingto the same procedure as Example 73 to give the title compound (22 mg,Yield 34%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.53 (br s, 1H), 7.91 (m, 1H), 6.80 (s,1H), 6.70 (s, 1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.93 (m, 1H), 3.80 (m,1H), 3.53 (m, 5H), 3.20 (m, 3H), 2.60 (m, 1H), 2.32 (m, 7H), 1.93 (m,2H), 1.68 (m, 2H), 1.53 (m, 4H)

Example 75 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)-acetamide

The compound (50 mg, 0.13 mmol) prepared in Example 27 and4-(3-aminopropyl)morpholine instead of morpholine were reacted accordingto the same procedure as Example 73 to give the title compound (23 mg,Yield 35%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.52 (br s, 1H), 7.94 (m, 1H), 6.79 (s,1H), 6.70 (s, 1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.93 (m, 1H), 3.80 (m,1H), 3.51 (m, 5H), 3.10 (m, 3H), 2.59 (m, 1H), 2.37 (m, 1H), 2.25 (m,6H), 1.93 (m, 2H), 1.68 (m, 2H), 1.53 (m, 6H)

Example 76 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide

The compound (50 mg, 0.13 mmol) prepared in Example 27 and methylamineinstead of morpholine were reacted according to the same procedure asExample 73 to give the title compound (45 mg, Yield 87%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.52 (br s, 1H), 7.90 (m, 1H), 6.80 (s,1H), 6.69 (s, 1H), 6.16 (s, 1H), 6.13 (m, 1H), 4.93 (m, 1H), 3.80 (m,1H), 3.55 (m, 1H), 3.15 (m, 1H), 2.58 (m, 4H), 2.39 (m, 1H), 1.93 (m,2H), 1.68 (m, 2H), 1.56 (m, 4H)

Example 77 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N,N-dimethyl-acetamide

The compound (50 mg, 0.13 mmol) prepared in Example 27 and dimethylamineinstead of morpholine were reacted according to the same procedure asExample 73 to give the title compound (26 mg, Yield 49%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.53 (br s, 1H), 6.79 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.93 (m, 1H), 3.81 (m, 1H), 3.63 (m,1H), 3.15 (m, 1H), 2.95 (s, 3H), 2.87 (m, 1H), 2.83 (s, 3H), 2.65 (m,1H), 1.93 (m, 2H), 1.69 (m, 2H), 1.53 (m, 4H)

Example 78 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-ethanone

The compound (40 mg, 0.11 mmol) prepared in Example 27 and1-methylpiperazine instead of morpholine were reacted according to thesame procedure as Example 73 to give the title compound (21 mg, Yield43%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.52 (br s, 1H), 6.80 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.94 (m, 1H), 3.80 (m, 1H), 3.62 (m,1H), 3.42 (m, 4H), 3.35 (m, 1H), 3.15 (m, 1H), 2.85 (m, 1H), 2.66 (m,1H), 2.24 (m, 4H), 2.13 (s, 3H), 1.93 (m, 2H), 1.68 (m, 2H), 1.55 (m,4H)

Example 79 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(3-dimethylamino-pyrrolidin-1-yl)-ethanone

The compound (40 mg, 0.11 mmol) prepared in Example 27 and3-dimethylaminopyrrolidine instead of morpholine were reacted accordingto the same procedure as Example 73 to give the title compound (24 mg,Yield 48%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.53 (br s, 1H), 6.80 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.94 (m, 1H), 3.81 (m, 1H), 3.62 (m,3H), 3.30 (m, 1H), 3.17 (m, 2H), 2.78 (m, 1H), 2.53 (m, 2H), 2.11 (s,3H), 2.07 (s, 3H), 1.93 (m, 2H), 1.69 (m, 3H), 1.59 (m, 5H)

Example 80 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone

The compound (40 mg, 0.11 mmol) prepared in Example 27 and3-pyrrolidinol instead of morpholine were reacted according to the sameprocedure as Example 73 to give the title compound (19 mg, Yield 40%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.54 (br s, 1H), 6.80 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.93 (m, 1H), 4.25 (m, 1H), 3.81 (m,1H), 3.63 (m, 3H), 3.47 (m, 2H), 3.32 (m, 2H), 3.17 (m, 1H), 2.79 (m,1H), 2.59 (m, 1H), 1.93 (m, 3H), 1.80 (m, 1H), 1.68 (m, 2H), 1.53 (m,4H)

Example 81 Synthesis of2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-piperidin-1-yl-ethanone

The compound (40 mg, 0.11 mmol) prepared in Example 27 and piperidineinstead of morpholine were reacted according to the same procedure asExample 73 to give the title compound (27 mg, Yield 57%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.52 (br s, 1H), 6.80 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.94 (m, 1H), 3.81 (m, 1H), 3.63 (m,1H), 3.45 (m, 1H), 3.38 (m, 3H), 3.14 (m, 1H), 2.85 (m, 1H), 1.93 (m,2H), 1.68 (m, 2H), 1.48 (m, 10H)

Example 82 Synthesis of2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-N-methyl-acetamide

The compound (44 mg, 0.11 mmol) prepared in Example 31 was dissolved inN,N-dimethylformamide (2 ml). Methylamine (0.08 ml, 2M in THF, 0.17mmol), EDC (36 mg, 0.19 mmol) and HOBT (30 mg, 0.22 mmol) were addedthereto, and the mixture was stirred for 8 h at room temperature. Aftercompletion of the reaction, saturated sodium bicarbonate solution wasadded. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure, and concentrated. The residue was purified bycolumn chromatography to give the title compound (18 mg, Yield 37%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.54 (br s, 1H), 7.91 (m, 1H), 6.81 (s,1H), 6.70 (s, 1H), 6.28 (s, 1H), 6.08 (m, 1H), 4.93 (m, 1H), 3.85 (m,2H), 3.56 (m, 2H), 3.44 (m, 2H), 3.15 (m, 1H), 2.06 (m, 4H), 2.37 (m,1H), 1.93 (m, 2H), 1.39 (m, 2H)

Example 83 Synthesis of2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-1-morpholin-4-yl-ethanone

The compound (44 mg, 0.11 mmol) prepared in Example 31 and morpholineinstead of methylamine were reacted according to the same procedure asExample 82 to give the title compound (35 mg, Yield 68%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.53 (br s, 1H), 6.81 (s, 1H), 6.70 (s,1H), 6.28 (s, 1H), 6.08 (m, 1H), 4.96 (m, 1H), 3.86 (m, 2H), 3.47 (m,12H), 3.15 (m, 1H), 2.85 (m, 1H), 2.69 (m, 1H), 1.94 (m, 2H), 1.39 (m,2H)

Example 84 Synthesis of2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-ethanone

The compound (100 mg, 0.28 mmol) prepared in Example 37 was dissolved inN,N-dimethylformamide (3 ml). 1-Methylpiperazine (36 mg, 0.36 mmol), EDC(90 mg, 0.47 mmol) and HOBT (75 mg, 0.55 mmol) were added thereto, andthe mixture was stirred for 8 h at room temperature. After completion ofthe reaction, saturated sodium bicarbonate solution was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and concentrated. The residue was purified by columnchromatography to give the title compound (78 mg, Yield 64%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.44 (br s, 1H), 6.73 (s, 1H), 6.52 (dd,1H), 6.19 (d, J=1.2 Hz, 1H), 6.07 (dd, 1H), 4.99 (m, 1H), 3.84 (m, 2H),3.65 (m, 1H), 3.49 (m, 4H), 3.20 (m, 1H), 2.88 (m, 1H), 2.71 (m, 1H),2.28 (m, 4H), 2.17 (s, 3H), 1.98 (m, 2H), 1.72 (m, 2H), 1.58 (m, 4H)

Example 85 Synthesis of2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide

The compound (100 mg, 0.28 mmol) prepared in Example 37 and4-(2-aminoethyl)morpholine instead of 1-methylpiperazine were reactedaccording to the same procedure as Example 84 to give the title compound(80 mg, Yield 60%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.46 (br s, 1H), 7.95 (m, 1H), 6.75 (s,1H), 6.73 (dd, 1H), 6.18 (d, J=4.0 Hz, 1H), 6.07 (dd, 1H), 5.00 (m, 1H),3.84 (m, 1H), 3.58 (m, 1H), 3.53 (m, 4H), 3.20 (m, 3H), 2.73 (m, 1H),2.45 (m, 3H), 2.34 (m, 4H), 1.98 (m, 2H), 1.72 (m, 2H), 1.59 (m, 4H)

Example 86 Synthesis of1-(4-acetyl-piperazin-1-yl)-2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanone

The compound (100 mg, 0.28 mmol) prepared in Example 37 and1-acetylpiperazine instead of 1-methylpiperazine were reacted accordingto the same procedure as Example 84 to give the title compound (60 mg,Yield 55%).

Example 87 Synthesis of2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide

The compound (83 mg, 0.22 mmol) prepared in Example 48 was dissolved inN,N-dimethylformamide (3 ml). Methylamine (0.17 ml, 2M in THF, 0.33mmol), EDC (72 mg, 0.38 mmol) and HOBT (60 mg, 0.44 mmol) were addedthereto, and the mixture was stirred for 8 h at room temperature. Aftercompletion of the reaction, saturated sodium bicarbonate solution wasadded. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure, and concentrated. The residue was purified bycolumn chromatography to give the title compound (39 mg, Yield 46%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.22 (br s, 1H), 7.90 (m, 1H), 6.61 (s,1H), 6.23 (s, 1H), 5.87 (m, 1H), 5.85 (s, 1H), 4.90 (m, 1H), 3.76 (m,1H), 3.64 (s, 3H), 3.52 (m, 1H), 3.12 (m, 1H), 2.58 (m, 4H), 2.35 (m,1H), 1.91 (m, 2H), 1.67 (m, 2H), 1.53 (m, 4H)

Example 88 Synthesis of2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone

The compound (83 mg, 0.22 mmol) prepared in Example 48 and morpholineinstead of methylamine were reacted according to the same procedure asExample 87 to give the title compound (24 mg, Yield 24%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.21 (br s, 1H), 6.62 (s, 1H), 6.24 (s,1H), 5.87 (m, 1H), 5.85 (s, 1H), 4.92 (m, 1H), 3.77 (m, 1H), 3.65 (s,3H), 3.60 (m, 1H), 3.58-3.33 (m, 8H), 3.13 (m, 1H), 2.84 (m, 1H), 2.66(m, 1H), 1.91 (m, 2H), 1.67 (m, 2H), 1.53 (m, 4H)

Example 89 Synthesis of2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-ethyl-acetamide

The compound (9 mg, 0.03 mmol) prepared in Example 42 was dissolved inN,N-dimethylformamide (1 ml). Ethylamine hydrochloride (3 mg, 0.03mmol), EDC (8 mg, 0.04 mmol), HOBT (5 mg, 0.04 mmol) and triethylamine(8 mg, 0.08 mmol) were added thereto, and the mixture was stirred for 8h at room temperature. After completion of the reaction, saturatedsodium bicarbonate solution was added. The mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and concentrated. Theresidue was purified by column chromatography to give the title compound(4 mg, Yield 41%).

¹H-NMR (400 HMz, CDCl₃); δ 9.66, 7.08˜6.99 (m, 2H), 6.92 (d, 1H), 6.55(d, J=7.2 Hz, 1H), 5.88 (m, 1H), 5.02 (m, 1H), 4.13 (m, 1H), 3.61 (m,1H), 3.32-3.18 (m, 3H), 2.67 (1H, m), 2.52 (m, 1H), 2.04 (m, 1H),1.72-1.53 (m, 6H), 1.08 (m, 3H)

Example 90 Synthesis of2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide

The compound (97 mg, 0.28 mmol) prepared in Example 42 and methylamineinstead of ethylamine were reacted according to the same procedure asExample 89 to give the title compound (34 mg, Yield 34%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.33 (br s, 1H), 7.90 (m, 1H), 6.78 (m,1H), 6.71 (s, 1H), 6.24 (s, 1H), 5.80 (m, 1H), 4.93 (m, 1H), 3.81 (m,1H), 3.54 (m, 1H), 3.14 (m, 1H), 2.62 (m, 1H), 2.58 (m, 3H), 2.38 (m,1H), 1.93 (m, 2H), 1.69 (m, 2H), 1.54 (m, 4H)

Example 91 Synthesis of2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone

The compound (97 mg, 0.28 mmol) prepared in Example 42 and morpholineinstead of ethylamine were reacted according to the same procedure asExample 89 to give the title compound (19 mg, Yield 16%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.32 (br s, 1H), 6.78 (m, 1H), 6.71 (s,1H), 6.24 (s, 1H), 5.81 (m, 1H), 4.95 (m, 1H), 3.81 (m, 1H), 3.61 (m,1H), 3.59-3.39 (m, 8H), 3.15 (m, 1H), 2.87 (m, 1H), 2.68 (m, 1H), 1.93(m, 2H), 1.68 (m, 2H), 1.54 (m, 4H)

Example 92 Synthesis ofN-methyl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetamide

The compound (80 mg, 0.22 mmol) prepared in Example 45 instead of thecompound prepared in Example 48 was reacted according to the sameprocedure as Example 87 to give the title compound (17 mg, Yield 20%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.34 (br s, 1H), 7.90 (m, 1H), 6.79 (m,1H), 6.72 (s, 1H), 6.33 (m, 1H), 5.76 (m, 1H), 4.93 (m, 1H), 3.86 (m,1H), 3.54 (m, 2H), 3.43 (m, 2H), 3.14 (m, 1H), 2.61 (m, 1H), 2.59 (m,3H), 2.38 (m, 1H), 1.95 (m, 2H), 1.40 (m, 2H)

Example 93 Synthesis of1-morpholin-4-yl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanone

The compound (80 mg, 0.22 mmol) prepared in Example 45 instead of thecompound prepared in Example 42 was reacted according to the sameprocedure as Example 91 to give the title compound (12 mg, Yield 13%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.34 (br s, 1H), 6.79 (m, 1H), 6.72 (s,1H), 6.33 (m, 1H), 5.77 (m, 1H), 4.95 (m, 1H), 3.87 (m, 1H), 3.61 (m,1H), 3.57-3.38 (m, 11H), 3.15 (m, 1H), 2.87 (m, 1H), 2.68 (m, 1H), 1.95(m, 2H), 1.40 (m, 2H)

Preparation 51: Synthesis of{5-chloro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (520 mg, 1.43 mmol) prepared in Example 28 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (524 mg, Yield 77%).

Example 94 Synthesis of{5-chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (52 mg, 0.11 mmol) prepared in Preparation 51 was dissolvedin N,N-dimethylformamide (4 ml). Dimethylamine (1.1 ml, 2M in THF, 2.2mmol) and potassium carbonate (300 mg, 2.17 mmol) were added thereto,and the mixture was stirred for 8 h at room temperature. Aftercompletion of the reaction, water was added. The mixture was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was distilled under reduced pressure, andconcentrated. The residue was purified by column chromatography to givethe title compound (29 mg, Yield 68%).

¹H-NMR (500 HMz, CDCl₃); δ 10.07 (br s, 1H), 6.99 (s, 1H), 6.80 (s, 1H),6.42 (s, 1H), 4.67 (m, 1H), 3.54 (m, 1H), 3.16 (m, 1H), 2.46 (m, 1H),2.37 (m, 1H), 2.19 (s, 6H), 2.02 (m, 3H), 1.81 (m, 4H), 1.69 (m, 4H)

Example 95 Synthesis of{5-chloro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (52 mg, 0.11 mmol) prepared in Preparation 51 andmorpholine instead of dimethylamine were reacted according to the sameprocedure as Example 94 to give the title compound (18 mg, Yield 38%).

¹H NMR (DMSO-d₆, ppm); δ 11.46 (1H, s), 6.79 (1H, s), 6.68 (1H, s), 6.11(1H, s), 6.09 (1H, d), 4.61 (1H, quin), 3.81 (1H, m), 3.57 (4H, m), 3.15(1H, m), 2.50-2.43 (3H, m), 2.35 (4H, m), 1.95 (2H, m), 1.80 (1H, m),1.68 (2H, m), 1.57-1.49 (4H, m), 1.21 (1H, m)

FAB MS (m/e)=434

Example 96 Synthesis of{5-chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (250 mg, 0.53 mmol) prepared in Preparation 51 wasdissolved in tetrahydrofuran (10 ml). 1-t-Butoxycarbonylpiperazine (980mg, 5.28 mmol) and potassium carbonate (730 mg, 5.28 mmol) were addedthereto, and the mixture was stirred for 8 h at 80° C. After completionof the reaction, water was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure.

Thus obtained compound was dissolved in dichloromethane (50 ml), and 4Nhydrochloric acid ethyl acetate solution (1.3 ml, 5.28 mmol) was addedthereto. The mixture was stirred for 4 h at room temperature. Aftercompletion of the reaction, the reaction solution was distilled underreduced pressure to give a solid. The solid was washed with ethylether,and dried to give the title compound (125 mg, Yield 55%).

¹H NMR (DMSO-d₆, ppm); δ 11.48 (1H, s), 6.79 (1H, s), 6.67 (1H, s), 6.11(1H, s), 6.10 (1H, d), 4.61 (1H, m), 3.80 (1H, m), 3.54 (1H, m), 3.15(1H, m), 2.93 (2H, m), 2.50-2.41 (2H, m), 2.31 (3H, m), 1.95 (4H, m),1.79 (1H, m), 1.68 (3H, m), 1.57-1.50 (4H, m), 1.20 (1H, m)

FAB MS (m/e)=432

Example 97 Synthesis of1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 and1-acetylpiperazine instead of dimethylamine were reacted according tothe same procedure as Example 94 to give the title compound (26 mg,Yield 33%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.47 (br s, 1H), 6.79 (s, 1H), 6.68 (s,1H), 6.16 (s, 1H), 6.11 (m, 1H), 4.62 (m, 1H), 3.80 (m, 1H), 3.55 (m,1H), 3.39 (m, 4H), 3.15 (m, 1H), 2.46 (m, 1H), 2.32 (m, 4H), 1.95 (m,4H), 1.80 (m, 1H), 1.68 (m, 2H), 1.53 (m, 4H)

Example 98 Synthesis of(5-chloro-2-{(R)-4-[2-(4-ethanesulfonyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine

The compound (40 mg, 0.11 mmol) prepared in Preparation 51 and1-ethylsulfonylpiperazine instead of dimethylamine were reactedaccording to the same procedure as Example 94 to give the title compound(17 mg, Yield 39%).

¹H-NMR (500 HMz, CDCl₃); δ 11.29 (br s, 1H), 6.97 (s, 1H), 6.86 (s, 1H),6.37 (s, 1H), 4.93 (m, 1H), 3.92 (br s, 1H), 3.77 (m, 1H), 3.57 (m, 1H),3.16 (m, 1H), 2.95 (m, 2H), 2.80 (m, 4H), 2.42-2.28 (m, 4H), 2.03 (m,4H), 1.74 (m, 3H), 1.63 (m, 4H), 1.43 (m, 1H), 1.32 (t, 3H)

Example 99 Synthesis of1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone

The compound (85 mg, 0.20 mmol) prepared in Example 96 was dissolved inN,N-dimethylformamide (1 ml). Glycolic acid (22 mg, 0.30 mmol), EDC (64mg, 0.33 mmol) and HOBT (53 mg, 0.39 mmol) were added thereto, and themixture was stirred for 8 h at room temperature. After completion of thereaction, saturated sodium bicarbonate solution was added. The mixturewas extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and concentrated. The residue was purified by columnchromatography to give the title compound (41 mg, Yield 44%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.47 (br s, 1H), 6.79 (s, 1H), 6.68 (s,1H), 6.16 (s, 1H), 6.10 (m, 1H), 4.63 (m, 1H), 4.50 (m, 1H), 4.04 (m,2H), 3.81 (m, 1H), 3.55 (m, 1H), 3.43 (m, 2H), 3.16 (m, 1H), 2.52 (m,2H), 2.35 (m, 4H), 1.95 (m, 3H), 1.81 (m, 1H), 1.68 (m, 2H), 1.53 (m,4H)

Example 100 Synthesis of(5-chloro-2-{(R)-4-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 and1-methylpiperazine instead of dimethylamine were reacted according tothe same procedure as Example 94 to give the title compound (24 mg,Yield 32%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.47 (br s, 1H), 6.79 (s, 1H), 6.67 (s,1H), 6.16 (s, 1H), 6.10 (m, 1H), 4.59 (m, 1H), 3.80 (m, 1H), 3.54 (m,1H), 3.15 (m, 1H), 2.40 (m, 10H), 2.13 (s, 3H), 1.95 (m, 3H), 1.78 (m,1H), 1.68 (m, 2H), 1.53 (m, 4H)

Example 101 Synthesis of1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperidin-4-ol

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 and4-hydroxypiperidine instead of dimethylamine were reacted according tothe same procedure as Example 94 to give the title compound (28 mg,Yield 37%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 6.79 (s, 1H), 6.68 (s,1H), 6.16 (s, 1H), 6.10 (m, 1H), 4.60 (m, 1H), 3.80 (m, 1H), 3.54 (m,1H), 3.32 (m, 4H), 3.16 (m, 1H), 2.71 (m 1H), 2.60 (m, 1H), 2.32 (m,5H), 1.71 (m, 5H), 1.57 (m, 5H)

Example 102 Synthesis of(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 and2-oxopiperazine instead of dimethylamine were reacted according to thesame procedure as Example 94 to give the title compound (38 mg, Yield51%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 7.71 (s, 1H), 6.79 (s,1H), 6.68 (s, 1H), 6.16 (s, 1H), 6.10 (m, 1H), 4.61 (m, 1H), 3.81 (m,1H), 3.55 (m, 1H), 3.13 (m, 3H), 2.92 (m, 2H), 2.56 (m 3H), 1.96 (m,3H), 1.80 (m, 1H), 1.68 (m, 2H), 1.53 (m, 4H)

Example 103 Synthesis of(5-chloro-2-{(R)-4-[2-(3-dimethylamino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 and3-dimethylaminopyrrolidine instead of dimethylamine were reactedaccording to the same procedure as Example 94 to give the title compound(21 mg, Yield 27%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.47 (br s, 1H), 6.79 (s, 1H), 6.67 (s,1H), 6.16 (s, 1H), 6.11 (m, 1H), 4.62 (m, 1H), 3.80 (m, 1H), 3.52 (m,1H), 3.15 (m, 1H), 2.66 (m, 2H), 2.56 (m 2H), 2.41 (m, 2H), 2.27 (m,1H), 1.93 (m, 3H), 1.71 (m, 4H), 1.53 (m, 4H)

Example 104 Synthesis of{5-chloro-2-[(R)-4-(2-piperidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 andpiperidine instead of dimethylamine were reacted according to the sameprocedure as Example 94 to give the title compound (30 mg, Yield 41%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.52 (br s, 1H), 6.80 (s, 1H), 6.70 (s,1H), 6.16 (s, 1H), 6.12 (m, 1H), 4.63 (m, 1H), 3.80 (m, 1H), 3.57 (m,1H), 3.29 (m, 4H), 3.17 (m, 1H), 2.60 (m, 4H), 1.95 (m, 3H), 1.68 (m,2H), 1.58 (m, 9H)

Example 105 Synthesis of(5-chloro-2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 andthiomorpholine-1,1-dioxide instead of dimethylamine were reactedaccording to the same procedure as Example 94 to give the title compound(3.1 mg, Yield 38%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 6.79 (s, 1H), 6.68 (s,1H), 6.16 (s, 1H), 6.09 (m, 1H), 4.61 (m, 1H), 3.80 (m, 1H), 3.56 (m,1H), 3.16 (m, 1H), 3.07 (m, 4H), 2.89 (m, 4H), 2.67 (m, 2H), 1.94 (m,3H), 1.81 (m, 1H), 1.68 (m, 2H), 1.53 (m, 4H)

Example 106 Synthesis of{5-chloro-2-[(R)-4-(2-pyrazol-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (81 mg, 0.11 mmol) prepared in Preparation 51 was dissolvedin tetrahydrofuran (4 ml). Pyrazole (58 mg, 0.85 mmol) and sodiumhydride (21 mg, 60%, 0.85 mmol) were added thereto, and the mixture wasstirred for 8 h at room temperature. After completion of the reaction,water was added. The mixture was extracted with ethyl acetate, driedover anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, and concentrated. The residue waspurified by column chromatography to give the title compound (24 mg,Yield 34%).

¹H NMR (DMSO-d₆, ppm); δ 11.50 (1H, s), 7.76 (1H, s), 7.42 (1H, s), 6.80(1H, s), 6.70 (1H, s), 6.22 (1H, s), 6.17 (1H, s), 6.11 (1H, d), 4.49(1H, quin), 4.32 (2H, m), 3.80 (1H, m), 3.53 (1H, t), 3.12 (1H, t), 2.38(1H, m), 2.14 (1H, m), 1.92 (2H, m), 1.68 (2H, m), 1.59-1.50 (4H, m)

FAB MS (m/e)=414

Example 107 Synthesis of(S)-1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidine-2-carboxylicacid

The compound (200 mg, 0.42 mmol) prepared in Preparation 51 wasdissolved in tetrahydrofuran (20 ml). Pyrrolidine-2-carboxylic acidmethyl ester hydrochloride (700 mg, 4.22 mmol) and potassium carbonate(1.2 g, 8.44 mmol) were added thereto, and the mixture was stirred for 8h at 80° C. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure.

Thus obtained compound was dissolved in tetrahydrofuran (10 ml),methanol (10 ml) and water (10 ml). Lithium hydroxide monohydrate (71mg, 1.70 mmol) was added thereto, and the mixture was stirred for 4 h atroom temperature. After completion of the reaction, 1N hydrochloric acidsolution was added. The mixture was extracted with ethyl acetate, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (34 mg, Yield 18%).

¹H NMR (CDCl₃, ppm); δ 12.04 (1H, s), 11.02 (1H, s), 6.85 (1H, s), 6.69(1H, s), 6.31 (1H, s), 6.24 (1H, m), 4.37 (1H, m), 4.10 (1H, m), 3.86(1H, m), 3.79 (1H, m), 3.59 (1H, m), 3.28 (1H, m), 3.17 (1H, m), 2.88(2H, m), 2.59 (1H, m), 2.21 (1H, m), 2.06-1.59 (11H, m), 1.23 (1H, m)

FAB MS (m/e)=461

Example 108 Synthesis of{5-chloro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (50 mg, 0.11 mmol) prepared in Preparation 51 was dissolvedin N,N-dimethylformamide (2 ml). Sodium methanesulfinate (54 mg, 0.55mmol) was added thereto, and the mixture was stirred for 8 h at roomtemperature. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and concentrated. The residue was purified by columnchromatography to give the title compound (19 mg, Yield 45%).

¹H-NMR (400 HMz, CDCl₃); δ 10.39 (br s, 1H), 7.03 (s, 1H), 6.89 (s, 1H),6.48 (s, 1H), 6.17 (s, 1H), 4.77 (m, 1H), 3.87 (m, 1H), 3.59 (m, 1H),3.29 (m, 1H), 3.17 (m, 2H), 2.86 (s, 3H), 2.26 (m, 2H), 2.10 (m, 2H),1.70 (m, 4H), 1.51 (m, 2H)

Example 109 Synthesis of3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester

The compound (150 mg, 0.31 mmol) prepared in Preparation 51 and5-methyl-3H-imidazole-4-carboxylic acid ethyl ester instead of pyrazolewere reacted according to the same procedure as Example 106 to give thetitle compound (74 mg, Yield 47%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.49 (br s, 1H), 7.71 (s, 1H), 6.80 (s,1H), 6.72 (s, 1H), 6.17 (s, 1H), 6.08 (m, 1H), 4.56 (m, 1H), 4.16 (m,4H), 3.81 (m, 1H), 3.58 (m, 1H), 3.18 (m, 1H), 2.46 (s, 3H), 2.11 (m,2H), 1.95 (m, 2H), 1.68 (m, 2H), 1.53 (m, 4H), 1.22 (m, 3H)

Example 110 Synthesis of3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylicacid

The compound (35 mg, 0.07 mmol) prepared in Example 109 was dissolved intetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). Lithiumhydroxide monohydrate (29 mg, 0.70 mmol) was added thereto, and themixture was stirred for 8 h at room temperature. After completion of thereaction, 1N hydrochloric acid solution was added. The mixture wasextracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give the title compound (17 mg, Yield 52%).

¹H NMR (DMSO-d₆, ppm); δ 11.50 (1H, s), 7.71 (1H, s), 6.80 (1H, s), 6.72(1H, s), 6.17 (1H, s), 6.08 (1H, m), 4.55 (1H, m), 4.13 (2H, m), 3.80(1H, m), 3.55 (2H, m), 2.19-2.15 (2H, m), 1.95 (3H, m), 1.68 (3H, m),1.51 (5H, m)

FAB MS (m/e)=472

Example 111 Synthesis of1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-2-one

The compound (80 mg, 0.22 mmol) prepared in Preparation 51 andpyrrolidinone instead of dimethylamine were reacted according to thesame procedure as Example 94 to give the title compound (17 mg, Yield36%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.49 (br s, 1H), 6.80 (s, 1H), 6.69 (s,1H), 6.16 (s, 1H), 4.51 (m, 1H), 3.80 (m, 1H), 3.57 (m, 1H), 3.46 (m,1H), 3.32 (m, 1H), 3.15 (m, 1H), 2.18 (m, 2H), 1.91 (m, 5H), 1.80 (m,1H), 1.68 (m, 2H), 1.53 (m, 4H)

Preparation 52: Synthesis of{5-chloro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (3.7 g, 10.2 mmol) prepared in Example 32 was dissolved intetrahydrofuran (100 ml). Imidazole (2.1 g, 30.6 mmol),triphenylphosphine (4.0 g, 15.3 mmol), and iodine (3.9 g, 15.3 mmol)were added thereto, and the mixture was stirred for 8 h at 0° C.˜roomtemperature. After completion of the reaction, ethyl acetate (100 ml)was added, and the mixture was washed with water (2×100 ml). The organiclayer was concentrated, and the residue was separated by columnchromatography to give the title compound (2.0 g, 4.07 mmol, Yield 40%).

Preparation 53: Synthesis of1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylicacid ethyl ester

The compound (300 mg, 0.63 mmol) prepared in Preparation 52 wasdissolved in N,N-dimethylformamide (20 ml). Piperidine-3-carboxylic acidethyl ester (1.97 ml, 12.7 mmol) and potassium carbonate (1.75 g, 12.7mmol) were added thereto, and the mixture was stirred for 4 h at roomtemperature. After completion of the reaction, 1N hydrochloric acidsolution was added. The mixture was extracted with ethyl acetate, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (150 mg, Yield 46%).

¹H NMR (DMSO-d₆, ppm); δ 11.48 (1H, s), 6.82 (1H, s), 6.67 (1H, s), 6.29(1H, s), 6.04 (1H, d), 4.61 (1H, quin), 4.47 (1H, m), 3.87 (2H, m), 3.62(2H, q), 3.56 (2H, m), 3.44-3.39 (4H, m), 3.14 (2H, m), 2.52 (1H, m),2.37-2.30 (6H, m), 1.96-1.92 (3H, m), 1.81 (1H, m), 1.42 (2H, m), 1.28(3H, t)

FAB MS (m/e)=519

Example 112 Synthesis of1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylicacid

The compound (135 mg, 0.28 mmol) prepared in Preparation 53 was reactedaccording to the same procedure as Example 110 to give the titlecompound (90 mg, Yield 58%).

¹H NMR (DMSO-d₆, ppm); δ 13.17 (1H, s), 11.94 (1H, s), 6.80 (1H, s),6.68 (1H, s), 6.28 (1H, s), 6.04 (1H, d), 4.62 (1H, quin), 4.47 (1H, m),3.87 (2H, m), 3.56 (2H, m), 3.44-3.39 (4H, m), 3.14 (2H, m), 2.52 (1H,m), 2.37-2.30 (6H, m), 1.96-1.92 (3H, m), 1.80 (1H, m), 1.40 (2H, m)

FAB MS (m/e)=491

Example 113 Synthesis of1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylicacid dimethylamide

The compound (84 mg, 0.18 mmol) prepared in Example 112 was dissolved inN,N-dimethylformamide (4 ml). Dimethylamine (0.13 ml, 2M in THF, 0.27mmol), EDC (58 mg, 0.30 mmol) and HOBT (48 mg, 0.35 mmol) were addedthereto, and the mixture was stirred for 8 h at room temperature. Aftercompletion of the reaction, saturated sodium bicarbonate solution wasadded. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure, and concentrated. The residue was purified bycolumn chromatography to give the title compound (18 mg, Yield 20%).

¹H NMR (DMSO-d₆, ppm); δ 11.48 (1H, s), 6.81 (1H, s), 6.69 (1H, s), 6.28(1H, s), 6.04 (1H, d), 4.60 (1H, quin), 3.87 (2H, m), 3.56 (2H, m), 3.44(2H, t), 3.16 (1H, m), 2.97 (3H, s), 2.95 (1H, m), 2.88-2.76 (2H, m),2.74 (5H, m), 1.96 (4H, m), 1.80 (2H, m), 1.66 (2H, m), 1.50-1.37 (3H,m), 1.23 (1H, m)

FAB MS (m/e)=518

Example 114 Synthesis of[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamicacid t-butyl ester

The compound (300 mg, 0.63 mmol) prepared in Preparation 52 and(S)-pyrrolidin-3-yl-carbamic acid t-butyl ester instead ofpiperidine-3-carboxylic acid ethyl ester were reacted according to thesame procedure as Preparation 53 to give the title compound (210 mg,Yield 61%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 6.92 (m, 1H), 6.81 (s,1H), 6.68 (s, 1H), 6.28 (m, 1H), 6.05 (m, 1H), 4.63 (m, 1H), 3.86 (m,3H), 3.59 (m, 1H), 3.54 (m, 1H), 3.44 (m, 2H), 3.14 (m, 1H), 2.71-2.58(m, 2H), 2.25 (m, 1H), 1.95 (m, 4H), 1.75 (m, 1H), 1.52 (m, 1H), 1.39(m, 2H), 1.37-1.32 (m, 11H)

Example 115 Synthesis of(2-{(R)-4-[2-((S)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound (150 mg, 0.27 mmol) prepared in Example 114 was dissolvedin dichloromethane (30 ml). 4N hydrochloric acid dioxane solution (0.34ml, 1.35 mmol) was added thereto, and the mixture was stirred for 4 h atroom temperature. After completion of the reaction, the reactionsolution was distilled under reduced pressure to give a solid. The solidwas washed with ethylether, and dried to give the title compound (92 mg,Yield 75%).

¹H NMR (DMSO-d₆, ppm); δ 10.92 (1H, s), 8.63 (2H, s, br), 6.86 (1H, s),6.83 (1H, s), 6.43 (1H, s), 6.11 (1H, m), 4.72 (1H, m), 3.65 (5H, m),3.45 (5H, m), 3.22 (3H, m), 2.37 (2H, m), 2.19 (3H, m), 1.90 (2H, m),1.49 (2H, m)

FAB MS (m/e)=448

Example 116 Synthesis ofN—[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-acetamide

The compound (85 mg, 0.19 mmol) prepared in Example 115 was dissolved indichloromethane (10 ml). Diisopropylethylamine (0.13 ml, 0.75 mmol) andacetyl chloride (0.013 ml, 0.19 mmol) were added thereto, and themixture was stirred for 30 min at room temperature. After completion ofthe reaction, water was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and concentrated. Theresidue was purified by column chromatography to give the title compound(39 mg, Yield 42%).

¹H NMR (DMSO-d₆, ppm); δ 11.49 (1H, s), 7.97 (1H, s), 6.81 (1H, s), 6.69(1H, s), 6.28 (1H, s), 6.05 (1H, d), 4.64 (1H, quin), 4.12 (1H, m), 3.85(2H, m), 3.53 (2H, m), 3.44 (2H, t), 3.34 (2H, m), 3.15 (1H, t),2.72-2.60 (3H, m), 2.39 (1H, m), 2.05-1.87 (4H, m), 1.80-1.72 (4H, m),1.53 (1H, m), 1.37 (2H, m),

FAB MS (m/e)=490

Example 117 Synthesis of{5-chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (100 mg, 0.2 mmol) prepared in Preparation 52 was reactedaccording to the same procedure as Example 96 to give the title compound(25 mg, Yield 30%).

¹H NMR (DMSO-d₆, ppm); δ 11.42 (1H, s), 6.83 (1H, s), 6.74 (1H, s), 6.30(1H, s), 6.02 (1H, d), 4.69 (1H, m), 3.85 (1H, m), 3.52-3.42 (6H, m),3.35 (3H, m), 3.20 (2H, m), 2.16 (2H, m), 1.92 (3H, m), 1.42 (3H, m)

FAB MS (m/e)=448

Example 118 Synthesis of1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone

The compound (23 mg, 0.05 mmol) prepared in Example 117 was dissolved inN,N-dimethylformamide (5 ml). Glycolic acid (15.1 mg, 0.2 mmol),triethylamine (28 ul, 0.2 mmol), EDC (45 mg, 0.23 mmol) and HOBT (40 mg,0.29 mmol) were added thereto, and the mixture was stirred for 8 h atroom temperature. After completion of the reaction, 1N hydrochloric acidsolution was added. The mixture was extracted with ethyl acetate, driedover anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, and purified by column chromatographyto give the title compound (5 mg, Yield 19%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 6.81 (s, 1H), 6.69 (d,J=1.8 Hz, 1H), 6.29 (s, 1H), 6.05 (d, J=7.4 Hz, 1H), 4.62 (m, 1H), 4.49(t, 1H), 4.04 (m, 2H), 3.87 (m, 2H), 3.56 (m, 1H), 3.45 (m, 4H), 3.29(m, 4H), 3.16 (m, 1H), 2.36 (m, 4H). 1.96 (m, 3H), 1.80 (m, 1H), 1.40(m, 2H)

Example 119 Synthesis of1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-tetrazol-1-yl-ethanone

The compound (61 mg, 0.14 mmol) prepared in Example 117 and1H-tetrazole-1-acetic acid instead of glycolic acid were reactedaccording to the same procedure as Example 118 to give the titlecompound (31 mg, Yield 48%).

¹H NMR (DMSO-d₆, ppm); δ 11.48 (1H, s), 9.26 (1H, s), 6.81 (1H, s), 6.70(1H, s), 6.29 (1H, s), 6.04 (1H, d), 5.60 (2H, s), 4.64 (1H, quin), 3.87(2H, m), 3.57 (2H, m), 3.47-3.41 (7H, m), 3.17 (2H, m), 2.58 (1H, m),2.39 (2H, m), 1.99-1.93 (4H, m), 1.81 (1H, m), 1.40 (2H, m)

FAB MS (m/e)=558

Example 120 Synthesis of1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-3,3,3-trifluoro-propan-1-one

The compound (66 mg, 0.15 mmol) prepared in Example 117 was dissolved indichloromethane (10 ml). Diisopropylethylamine (0.08 ml, 0.44 mmol) and3,3,3-trifluoropropionic acid 2,5-dioxo-pyrrolidin-1-yl ester (29 mg,0.13 mmol) were added thereto, and the mixture was stirred for 8 h atroom temperature. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (6 mg, Yield 9%).

¹H NMR (DMSO-d₆, ppm); δ 11.47 (1H, s), 6.81 (1H, s), 6.69 (1H, s), 6.28(1H, s), 6.09 (1H, d), 4.62 (1H, quin), 3.87 (2H, m), 3.56 (4H, m),3.47-3.38 (7H, m), 3.16 (1H, m), 2.53 (1H, m), 2.3702.30 (4H, m), 1.94(3H, m), 1.81 (1H, m), 1.40 (2H, m)

FAB MS (m/e)=558

Example 121 Synthesis of[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-furan-2-yl-methanone

The compound (100 mg, 0.20 mmol) prepared in Preparation 52 andfuranoylpiperazine instead of piperidine-3-carboxylic acid ethyl esterwere reacted according to the same procedure as Preparation 53 to givethe title compound (19 mg, Yield 17%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 7.79 (s, 1H), 6.81 (s,1H), 6.69 (s, 1H), 6.59 (m, 1H), 6.28 (s, 1H), 6.05 (m, 1H), 4.63 (m,1H), 3.86 (m, 2H), 3.57 (m, 6H), 3.44 (m, 2H), 3.16 (m, 2H), 2.56 (m,1H), 1.96 (m, 3H), 1.83 (m, 1H), 1.41 (m, 2H)

Example 122 Synthesis of(5-chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2]bipyrazinyl-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound (100 mg, 0.20 mmol) prepared in Preparation 52 and1-(2-pyrazinyl)piperazine instead of piperidine-3-carboxylic acid ethylester were reacted according to the same procedure as Preparation 53 togive the title compound (13 mg, Yield 12%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.48 (br s, 1H), 8.27 (s, 1H), 8.04 (s,1H), 7.80 (s, 1H), 6.81 (s, 1H), 6.69 (s, 1H), 6.29 (s, 1H), 6.05 (m,1H), 4.64 (m, 1H), 3.86 (m, 2H), 3.57 (m, 2H), 3.53 (m, 4H), 3.18 (m,1H), 2.57 (m, 1H). 1.99 (m, 1H), 1.95 (m, 2H), 1.83 (m, 1H), 1.40 (m,2H)

Example 123 Synthesis of(5-chloro-2-{(R)-4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound (100 mg, 0.20 mmol) prepared in Preparation 52 and1-(2-pyrimidyl)piperazine instead of piperidine-3-carboxylic acid ethylester were reacted according to the same procedure as Preparation 53 togive the title compound (10 mg, Yield 9%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.49 (br s, 1H), 8.31 (m, 1H), 6.81 (s,1H), 6.69 (s, 1H), 6.58 (m, 1H), 6.28 (s, 1H), 6.06 (m, 1H), 4.65 (m,1H), 3.86 (m, 2H), 3.69 (m, 4H), 3.58 (m, 2H), 3.45 (m, 2H), 3.35 (m,1H), 3.18 (m, 1H), 2.56 (m, 1H). 2.43 (m, 3H), 2.00 (m, 1H), 1.96 (m,2H), 1.40 (m, 2H)

Preparation 54: Synthesis ofcyclopentyl-{5-fluoro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (120 mg, 0.35 mmol) prepared in Example 39 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (110 mg, Yield 70%).

Example 124 Synthesis of{2-[(R)-4-(2-amino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-cyclopentyl-amine

(Step 1)

The compound (100 mg, 0.22 mmol) prepared in Preparation 54 wasdissolved in N,N-dimethylformamide (2 ml). Sodium azide (43 mg, 0.66mmol) was added thereto, and the mixture was stirred for 1 h at 70° C.After completion of the reaction, water was added. The mixture wasextracted with ethyl acetate, dried over anhydrous magnesium sulfate,and filtered. The filtrate was distilled under reduced pressure, andpurified by column chromatography to give an azido compound (75 mg,Yield 9%).

(Step 2)

The compound (70 mg, 0.19 mmol) prepared in Step 1 was dissolved intetrahydrofuran (3 ml). Water (4 ul, 0.21 mmol) and triphenylphosphine(55 mg, 0.3.1 mmol) were added thereto, and the mixture was stirred for2 h at 80° C. After completion of the reaction, the reaction solutionwas distilled under reduced pressure, and purified by columnchromatography to give the title compound (45 mg, Yield 69%).

¹H-NMR (400 HMz, CDCl₃/DMSO-d₆); δ 11.28 (br s, 1H), 6.80 (br s, 2H),6.80 (d, J=2.0 Hz), 6.50 (dd, 1H), 6.16 (dd, 1H), 4.58 (m, 1H), 3.81 (m,1H), 3.54 (m, 1H), 3.24 (m, 2H), 3.02 (m, 1H), 2.13-1.55 (m, 10H)

Preparation 55: Synthesis of methanesulfonic acid2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethylester

The compound (1.0 g, 2.87 mmol) prepared in Example 39 was reactedaccording to the same procedure as Preparation 22 to give the titlecompound (1.1 g, Yield 90%).

Example 125 Synthesis of1-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone

The compound (100 mg, 0.23 mmol) prepared in Preparation 55 wasdissolved in N,N-dimethylformamide (10 ml). Triethylamine (48 mg, 0.47mmol) and 1-acetylpiperazine (92 mg, 0.70 mmol) were added thereto, andthe mixture was stirred for 8 h at 50° C. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, and purified by column chromatographyto give the title compound (60 mg, Yield 56%).

¹H-NMR (400 HMz, CDCl₃); δ 10.47 (br s, 1H), 6.87 (s, 1H), 6.66 (d,J=8.0 Hz, 1H), 6.26 (d, J=12.0 Hz, 1H), 4.80 (m, 1H), 3.92 (m, 1H), 3.81(m, 1H), 3.59 (m, 2H), 3.49 (m, 1H), 3.28 (m, 1H), 3.18 (m, 1H), 2.44(m, 2H), 2.34 (m, 1H), 2.23 (m, 2H), 2.14 (m, 1H), 2.05 (s, 3H), 1.93(m, 1H), 1.81 (m, 1H), 1.71 (m, 5H), 1.48 (m, 2H)

Example 126 Synthesis ofcyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 55 andmorpholine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 125 to give the title compound (50 mg, Yield52%).

¹H-NMR (400 HMz, CDCl₃); δ 10.92 (br s, 1H), 6.87 (s, 1H), 6.64 (d,J=8.0 Hz, 1H), 6.24 (d, J=12.0 Hz, 1H), 4.83 (m, 1H), 3.93 (m, 1H), 3.77(m, 1H), 3.54 (m, 4H), 3.47 (m, 1H), 3.17 (m, 1H), 2.38 (m, 1H), 2.33(m, 2H), 2.16 (m, 2H), 2.04 (m, 3H), 1.77 (m, 1H), 1.65 (m, 4H), 1.47(m, 1H), 1.35 (m, 1H)

Example 127 Synthesis ofcyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 55 anddimethylamine instead of 1-acetylpiperazine were reacted according tothe same procedure as Example 125 to give the title compound (40 mg,Yield 47%).

¹H-NMR (400 HMz, CDCl₃); δ 10.99 (br s, 1H), 6.80 (s, 1H), 6.60 (d,J=8.0 Hz, 1H), 6.22 (d, J=12.0 Hz, 1H), 4.59 (m, 1H), 4.13 (m, 1H), 3.47(m, 1H), 3.03 (m, 1H), 2.90 (m, 1H), 2.55 (m, 1H), 2.42 (s, 6H), 2.01(m, 3H), 1.81 (m, 1H), 1.62 (m, 2H), 1.55 (m, 4H)

Example 128 Synthesis ofcyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 55 andpyrrolidine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 125 to give the title compound (30 mg, Yield33%).

¹H-NMR (400 HMz, CDCl₃); δ 11.39 (br s, 1H), 6.81 (s, 1H), 6.63 (dd,1H), 6.25 (dd, 1H), 4.59 (m, 1H), 4.17 (m, 1H), 3.89 (m, 1H), 3.32 (m,1H), 3.07 (m, 3H), 2.71 (m, 1H), 2.09 (m, 2H), 1.95 (m, 4H), 1.77 (m,2H), 1.65 (m, 4H)

Example 129 Synthesis ofcyclopentyl-(2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-1H-indol-7-yl)-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 55 andthiomorpholine-1,1-dioxide instead of 1-acetylpiperazine were reactedaccording to the same procedure as Example 125 to give the titlecompound (10 mg, Yield 9%).

¹H-NMR (400 HMz, CDCl₃); δ 11.05 (br s, 1H), 6.94 (s, 1H), 6.60 (d,J=8.0 Hz, 1H), 6.26 (d, J=12.0 Hz, 1H), 4.74 (m, 1H), 3.85 (m, 1H), 3.62(t, 1H), 3.49 (q, 1H), 3.18 (q, 1H), 3.00 (m, 8H), 2.74 (m, 2H), 2.05(m, 3H), 1.79 (m, 2H), 1.63 (m, 4H)

Example 130 Synthesis of4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one

The compound (200 mg, 0.44 mmol) prepared in Preparation 55 wasdissolved in tetrahydrofuran (5 ml). 2-Oxopiperazine (87 mg, 0.88 mmol)and potassium carbonate (118 mg, 0.88 mmol) were added thereto, and themixture was stirred for 8 h at room temperature. After completion of thereaction, water was added. The mixture was extracted with ethyl acetate,dried over anhydrous magnesium sulfate, and filtered. The filtrate wasdistilled under reduced pressure, and purified by column chromatographyto give the title compound (650 mg, Yield 27%).

¹H-NMR (400 HMz, CDCl₃); δ 11.26 (br s, 1H), 7.26 (br s, 1H), 6.87 (s,1H), 6.58 (d, J=8.0 Hz, 1H), 6.22 (d, J=12.0 Hz, 1H), 4.73 (m, 1H), 3.84(m, 1H), 3.53 (t, 1H), 3.19 (m, 5H), 2.57 (m, 4H), 2.04 (m, 3H), 1.95(m, 1H), 1.74 (m, 2H), 1.62 (m, 2H)

Example 131 Synthesis of1-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone

The compound (500 mg, 1.09 mmol) prepared in Preparation 55 was reactedaccording to the same procedures as Example 96 and Example 99 to givethe title compound (100 mg, Yield 19%).

¹H-NMR (400 HMz, CDCl₃); δ 11.26 (br s, 1H), 6.89 (s, 1H), 6.63 (d,J=8.0 Hz, 1H), 6.22 (d, J=12.0 Hz, 1H), 4.85 (m, 1H), 4.10 (s, 2H), 3.77(m, 1H), 3.57 (m, 2H), 3.41 (m, 1H), 3.14 (q, 1H), 3.00 (m, 1H), 2.91(m, 1H), 2.38 (m, 3H), 2.12 (m, 2H), 2.02 (m, 4H), 1.85 (m, 1H), 1.77(m, 1H), 1.63 (m, 4H), 1.36 (m, 1H), 1.26 (m, 1H)

Example 132 Synthesis ofcyclopentyl-{5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (50 mg, 0.12 mmol) prepared in Preparation 55 and sodiumiodide (88 mg, 0.59 mmol) were dissolved in N,N-dimethylformamide (5ml), and stirred for 6 h at 50° C. Sodium methanesulfinate (60 mg, 0.59mmol) was added thereto, and the mixture was stirred for 8 h at roomtemperature. After completion of the reaction, water was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (14 mg, Yield 29%).

¹H-NMR (400 HMz, CDCl₃); δ 9.89 (br s, 1H), 6.87 (s, 1H), 6.67 (dd, 1H),6.28 (dd, 1H), 4.77 (m, 1H), 3.83 (t, 1H), 3.59 (m, 1H), 3.31 (m, 1H),3.13 (m, 2H), 2.84 (s, 3H), 2.27 (m, 2H), 2.04 (m, 2H), 1.68 (m, 6H),1.51 (m, 2H)

Preparation 56: Synthesis of methanesulfonic acid2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethylester

The compound (740 mg, 2.03 mol) prepared in Example 44 was reactedaccording to the same procedure as Preparation 22 to give the titlecompound (750 mg, Yield 84%).

Example 133 Synthesis of{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 56 anddimethylamine instead of 1-acetylpiperazine were reacted according tothe same procedure as Example 125 to give the title compound (21 mg,Yield 23%).

¹H-NMR (400 HMz, CDCl₃); δ 11.27 (br s, 1H), 6.79 (s, 1H), 6.60 (d,J=8.0 Hz, 1H), 6.22 (d, J=12.0 Hz, 1H), 4.61 (m, 1H), 4.13 (m, 2H), 3.59(m, 4H), 3.04 (m, 1H), 2.55 (s, 4H), 2.04 (m, 6H), 1.65 (m, 2H), 1.26(m, 2H)

Example 134 Synthesis of{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 56 andpyrrolidine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 125 to give the title compound (29 mg, Yield30%).

¹H-NMR (400 HMz, CDCl₃); δ 11.16 (br s, 1H), 6.87 (s, 1H), 6.68 (d,J=8.0 Hz, 1H), 6.26 (d, J=12.0 Hz, 1H), 4.69 (m, 1H), 4.17 (d, J=8.0 Hz,2H), 3.60 (m, 5H), 3.17 (m, 1H), 2.90 (m, 1H), 2.67 (m, 5H), 2.09 (m,3H), 1.90 (m, 4H), 1.57 (m, 2H)

Example 135 Synthesis of{5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 56 andmorpholine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 125 to give the title compound (16 mg, Yield16%).

¹H-NMR (400 HMz, CDCl₃); δ 11.16 (br s, 1H), 6.86 (s, 1H), 6.64 (d,J=8.0 Hz, 1H), 6.23 (d, J=12.0 Hz, 1H), 4.75 (m, 1H), 4.02 (m, 1H), 3.66(m, 4H), 3.51 (m, 4H), 3.18 (m, 1H), 2.60 (m, 1H), 2.49 (m, 4H), 2.07(m, 4H), 1.80 (m, 1H), 1.54 (m, 2H)

Example 136 Synthesis of1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl-piperazin-1-yl)-ethanone

The compound (100 mg, 0.23 mmol) prepared in Preparation 56 and1-acetylpiperazine were reacted according to the same procedure asExample 125 to give the title compound (24 mg, Yield 22%).

¹H-NMR (400 HMz, CDCl₃); δ 10.20 (br s, 1H), 6.87 (s, 1H), 6.68 (d,J=8.0 Hz, 1H), 6.27 (d, J=12.0 Hz, 1H), 4.76 (m, 1H), 4.01 (m, 3H), 3.61(m, 4H), 3.30 (m, 2H), 3.20 (m, 1H), 2.51 (m, 2H), 2.33 (m, 4H), 2.06(m, 7H), 1.99 (m, 1H), 1.49 (m, 2H)

Example 137 Synthesis of(2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 56 andthiomorpholine-1,1-dioxide instead of 1-acetylpiperazine were reactedaccording to the same procedure as Example 125 to give the titlecompound (28 mg, Yield 25%).

¹H-NMR (400 HMz, CDCl₃); δ 6.93 (s, 1H), 6.64 (d, J=8.0 Hz, 1H), 6.28(d, J=12.0 Hz, 1H), 4.68 (m, 1H), 4.03 (m, 2H), 3.55 (m, 3H), 3.26 (m,2H), 3.17 (m, 3H), 3.05 (m, 4H), 2.95 (m, 1H), 2.82 (m, 1H), 2.09 (m,4H), 1.82 (m, 1H), 1.65 (m, 2H)

Example 138 Synthesis of(5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine

The compound (50 mg, 0.11 mmol) prepared in Preparation 56 was reactedaccording to the same procedure as Example 132 to give the titlecompound (18 mg, Yield 38%).

¹H-NMR (400 HMz, CDCl₃); δ 10.15 (br s, 1H), 6.86 (s, 1H), 6.65 (dd,1H), 6.26 (dd, 1H), 4.77 (m, 1H), 4.05 (m, 1H), 3.56 (m, 4H), 3.36 (m,1H), 3.24 (m, 2H), 3.12 (m, 1H), 2.91 (s, 3H), 2.32 (m, 1H), 2.22 (m,1H), 2.13 (m, 1H), 2.02 (m, 1H), 1.54 (m, 2H)

Preparation 57: Synthesis of{5-fluoro-2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (3.2 g, 8.82 mol) prepared in Example 41 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (1.9 g, Yield 46%).

Example 139 Synthesis of4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one

The compound (200 mg, 0.44 mmol) prepared in Preparation 57 was reactedaccording to the same procedure as Example 130 to give the titlecompound (50 mg, Yield 51%).

¹H-NMR (400 HMz, CDCl₃); δ 11.07 (br s, 1H), 7.70 (br s, 1H), 6.83 (s,1H), 6.61 (d, J=8.0 Hz, 1H), 6.22 (d, J=12.0 Hz, 1H), 5.19 (m, 1H), 4.71(m, 1H), 4.05 (d, J=12.0 Hz, 2H), 3.55 (m, 4H), 3.33 (m, 3H), 3.14 (m,1H), 2.73 (m, 4H), 2.10 (m, 2H), 1.98 (m, 2H), 1.58 (m, 4H)

Example 140 Synthesis of1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone

The compound (500 mg, 1.06 mmol) prepared in Preparation 57 was reactedaccording to the same procedures as Example 96 and Example 97 to givethe title compound (100 mg, Yield 19%).

¹H-NMR (400 HMz, CDCl₃); δ 11.19 (br s, 1H), 6.89 (s, 1H), 6.65 (d,J=8.0 Hz, 1H), 6.23 (d, J=12.0 Hz, 1H), 4.82 (m, 1H), 4.20 (m, 1H), 4.18(s, 2H), 3.98 (m, 2H), 3.61 (m, 2H), 3.47 (m, 4H), 3.16 (m, 3H), 2.42(m, 3H), 2.17 (m, 5H), 1.90 (m, 2H), 1.40 (m, 2H)

Preparation 58: Synthesis ofcyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (1.68 g, 5.10 mol) prepared in Example 44 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (1.75 g, Yield 78%).

Example 141 Synthesis ofcyclopentyl-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (100 mg, 0.23 mmol) prepared in Preparation 58 wasdissolved in tetrahydrofuran (20 ml). Sodium methoxide (61 mg, 1.15mmol) was added thereto, and the mixture was stirred for 8 h at 80° C.After completion of the reaction, water was added. The mixture wasextracted with ethyl acetate, dried over anhydrous magnesium sulfate,and filtered. The filtrate was distilled under reduced pressure, andpurified by column chromatography to give the title compound (15 mg,Yield 19%).

¹H-NMR (500 HMz, DMSO-d₆); δ 10.62 (br s, 1H), 7.03 (d, J=7.95 Hz, 1H),6.99 (t, 1H), 6.93 (s, 1H), 6.48 (d, J=7.35 Hz, 1H), 4.83 (m, 1H), 3.83(m, 1H), 3.56 (m, 1H), 3.46 (m, 2H), 3.20 (m, 4H), 2.05-1.87 (m, 4H),1.70-1.38 (m, 6H)

Example 142 Synthesis ofcyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (150 mg, 0.34 mmol) prepared in Preparation 58 anddimethylamine instead of 2-oxopiperazine were reacted according to thesame procedure as Example 130 to give the title compound (38 mg, Yield31%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.28 (br s, 1H), 6.78 (m, 2H), 6.24 (m,2H), 5.80 (m, 1H), 4.59 (m, 1H), 3.81 (m, 1H), 3.51 (m, 1H), 3.13 (m,1H), 2.50 (m, 1H), 2.37 (m, 1H), 2.17 (s, 6H), 1.93 (m, 3H). 1.79-1.65(m, 3H), 1.54 (m, 4H)

Example 143 Synthesis ofcyclopentyl-{2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (150 mg, 0.34 mmol) prepared in Preparation 58 andmorpholine instead of 2-oxopiperazine were reacted according to the sameprocedure as Example 130 to give the title compound (48 mg, Yield 35%).

¹H-NMR (500 HMz, DMSO-d₆); δ 11.27 (br s, 1H), 6.78 (m, 2H), 6.70 (m,1H), 6.24 (m, 1H), 5.80 (m, 1H), 4.60 (m, 1H), 3.81 (m, 1H), 3.55-3.49(m, 4H), 3.13 (m, 1H), 2.46 (m, 1H), 2.36 (m, 4H), 1.96 (m, 3H). 1.80(m, 1H), 1.68 (m, 2H), 1.54 (m, 4H)

Example 144 Synthesis ofcyclopentyl-{2-[(R)-4-(2-piperidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

(Step 1)

Methyl ester compound (68 mg, 0.19 mmol) prepared from the compound ofStep 1 of Example 42 was dissolved in dichloromethane (4 ml).Diisobutylaluminum hydridie (0.13 ml, 1.5M in CH₂Cl₂, 0.21 mmol) wasadded at −78° C., and the mixture was stirred for 2 h. After completionof the reaction, potassium sodium tartrate solution was added. Themixture was extracted with ethyl acetate, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reduced pressureto give an aldehyde compound (62 mg, Yield 100%).

(Step 2)

The aldehyde compound (23 mg, 0.07 mmol) prepared in Step 1 wasdissolved in dichloroethane (2 ml). Piperidine (9 mg, 0.11 mmol) andsodium triacetoxyborohydride (19 mg, 0.09 mmol) were added thereto, andthe mixture was stirred for 30 min at room temperature. After completionof the reaction, water was added. The mixture was extracted with ethylacetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give the title compound (10 mg, Yield 36%).

¹H-NMR (400 HMz, CDCl₃); δ 10.34 (br s, 1H), 7.04 (d, 1H), 6.99 (t, 1H),6.49 (d, 1H), 4.72 (m, 1H), 3.86 (m, 1H), 3.51 (m, 1H), 3.15 (m, 1H),2.30˜2.00 (m, 8H), 2.69˜1.40 (m, 14H)

Preparation 59: Synthesis of{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (340 mg, 0.98 mol) prepared in Example 46 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (370 mg, Yield 83%).

Example 145 Synthesis of{2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (50 mg, 0.11 mmol) prepared in Preparation 59 was reactedaccording to the same procedure as Example 108 to give the titlecompound (18 mg, Yield %).

¹H-NMR (400 HMz, CDCl₃); δ 10.02 (br s, 1H), 7.08 (d, 1H), 7.00 (t, 1H),6.95 (s, 1H), 6.54 (d, 1H), 4.78 (m, 1H), 4.01 (m, 2H), 3.61-3.47 (m,4H), 3.33 (m, 1H), 3.15 (m, 2H), 2.85 (s, 3H), 2.25 (m, 2H). 2.05 (m,2H), 1.51 (m, 2H)

Preparation 60: Synthesis of2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl]-ethanol

The compound (2.40 g, 6.19 mmol) prepared in Example 47 was reactedaccording to the same procedure as Example 70 to give the title compound(1.20 g, Yield 54%).

Preparation 61: Synthesis ofcyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methoxy-1H-indol-7-yl}-amine

The compound (1.20 g, 3.34 mmol) prepared in Preparation 60 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (1.23 g, Yield 78%).

Example 146 Synthesis of1-(4-{2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone

The compound (500 mg, 1.07 mmol) prepared in Preparation 61 was reactedaccording to the same procedures as Example 96 and Example 97 to givethe title compound (20 mg, Yield 4%).

¹H-NMR (400 HMz, CDCl₃); δ 11.13 (br s, 1H), 6.98 (s, 1H), 6.42 (s, 1H),6.13 (d, 1H), 4.85 (m, 1H), 4.07 (s, 2H), 3.81 (m, 8H), 3.55 (m, 2H),3.39 (m, 1H), 3.13 (m, 1H), 2.96 (m, 1H), 2.90 (m, 1H), 2.35 (m, 3H),2.10 (m, 2H), 1.99 (m, 3H), 1.84 (m, 1H), 1.75 (m, 1H), 1.62 (m, 4H),1.44 (m, 1H), 1.35 (m, 1H)

Preparation 62: Synthesis of2-{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol

The compound (4.00 g, 9.91 mmol) prepared in Example 50 was reactedaccording to the same procedure as Example 70 to give the title compound(2.80 g, Yield 75%).

Preparation 63: Synthesis of{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methoxy-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine

The compound (2.80 g, 7.46 mmol) prepared in Preparation 62 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (2.65 g, Yield 73%).

Example 147 Synthesis of2-hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-ethanone

The compound (500 mg, 1.03 mmol) prepared in Preparation 63 was reactedaccording to the same procedures as Example 96 and Example 97 to givethe title compound (50 mg, Yield 10%).

¹H-NMR (400 HMz, CDCl₃); δ 11.13 (br s, 1H), 6.91 (s, 1H), 6.47 (s, 1H),6.17 (s, 1H), 4.86 (m, 1H), 4.13 (m, 2H), 3.97 (m, 3H), 3.84 (m, 3H),3.62 (m, 2H), 3.47 (m, 4H), 3.03 (m, 3H), 2.43 (m, 3H), 2.17 (m, 5H),1.98 (m, 3H), 1.44 (m, 2H)

Preparation 64: Synthesis of3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The acid compound (2.0 g, 8.3 mmol) prepared in Preparation 33 and thecompound (R)-4-amino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid ethylester hydrochloride (3.4 g, 10.2 mmol) prepared in Preparation 17 werereacted according to the same procedure as Preparation 34 to give thetitle compound (0.76 g, Yield: 26%).

¹H-NMR (400 HMz, CDCl₃); δ 10.00 (br s, 1H), 7.08 (s, 1H), 6.80 (s, 1H),6.57 (s, 1H), 4.71 (m, 1H), 4.07 (m, 2H), 3.88 (br s, 2H), 3.55 (m, 1H),3.11 (m, 1H), 2.50 (t, 2H), 2.05 (m, 2H), 1.22 (t, 3H)

Example 148 Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (760 mg, 2.1 mmol) prepared in Preparation 64 was reactedaccording to the same procedure as Example 26 to give the title compound(450 mg, Yield 51%).

Preparation 65: Synthesis of(R)-4-amino-5-(4-methoxy-benzylsulfanyl)-pentanoic acid cyclohexyl esterhydrochloride

(R)-4-t-butoxycarbonylamino-5-hydroxy-pentanoic acid cyclohexyl ester(6.5 g, 20.6 mmol) was reacted according to the same procedure asPreparation 17 to give the title compound (7.5 g, Yield 97%).

Preparation 66: Synthesis of3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid cyclohexyl ester

The compound (3.9 g, 16.2 mmol) prepared in Preparation 33 and thecompound (7.5 g, 19.5 mmol) prepared in Preparation 65 were reactedaccording to the same procedure as Preparation 34 to give the titlecompound (2.6 g, Yield 40%).

Preparation 67: Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid cyclohexyl ester

The compound (1.30 g, 3.20 mmol) prepared in Preparation 66 was reactedaccording to the same procedure as Example 29 to give the title compound(1.15 g, Yield 76%).

Example 149 Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The ester compound (500 mg, 1.05 mmol) prepared in Preparation 67 wasreacted according to the same procedure as Example 27 to give the titlecompound (400 mg, Yield 97%).

¹H-NMR (400 HMz, DMSO-d₆, Na salt); δ 11.69 (br s, 1H), 6.82 (d, J=4.0Hz, 1H), 6.68 (s, 1H), 6.27 (s, 1H), 6.18 (s, 1H), 4.63 (m, 1H), 3.83(m, 1H), 3.50 (m, 1H), 3.13 (m, 1H), 2.08˜1.96 (m, 6H), 1.72 (m, 2H),1.58 (m, 4H)

Example 150 Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propan-1-ol

The compound (650 mg, 1.37 mmol) prepared in Preparation 67 was reactedaccording to the same procedure as Example 70 to give the title compound(210 mg, Yield 41%).

¹H-NMR (400 HMz, CDCl₃); δ 10.42 (br s, 1H), 6.94 (s, 1H), 6.82 (s, 1H),6.37 (s, 1H), 4.58 (m, 1H), 4.56 (m, 1H), 3.75 (m, 2H), 3.65 (m, 1H),1.95 (m, 7H), 1.51 (m, 4H), 1.31 (m, 2H)

Preparation 68: Synthesis of3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propionicacid cyclohexyl ester

The compound (1.30 g, 3.20 mmol) prepared in Preparation 66 was reactedaccording to the same procedure as Example 30 to give the title compound(1.24 g, Yield 79%).

Example 151 Synthesis of3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propionicacid

The ester compound (500 mg, 1.05 mmol) prepared in Preparation 68 wasreacted according to the same procedure as Example 27 to give the titlecompound (250 mg, Yield 59%).

¹H-NMR (400 HMz, DMSO-d₆, Na salt); δ 11.53 (br s, 1H), 6.86 (s, 1H),6.76 (s, 1H), 6.34 (s, 1H), 4.67 (m, 1H), 3.91 (m, 2H), 3.49 (m, 4H),3.21 (m, 1H), 2.50 (m, 2H), 2.01 (m, 4H), 1.43 (m, 2H)

Example 152 Synthesis of3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propan-1-ol

The compound (650 mg, 1.33 mmol) prepared in Preparation 68 was reactedaccording to the same procedure as Example 70 to give the title compound(150 mg, Yield 29%).

¹H-NMR (400 HMz, CDCl₃); δ 11.00 (br s, 1H), 6.93 (s, 1H), 6.82 (s, 1H),6.31 (s, 1H), 4.89 (br s, 1H), 4.56 (m, 1H), 3.95 (m, 1H), 3.85 (m, 1H),3.77 (m, 1H), 3.65 (m, 1H), 3.51 (m, 4H), 3.10 (m, 1H), 1.97 (m, 2H),1.83 (m, 3H), 1.74 (m, 1H), 1.44 (m, 1H), 1.40 (m, 1H)

Example 153 Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-propionamide

The compound (150 mg, 0.38 mmol) prepared in Example 149 and4-(2-aminoethyl)morpholine instead of morpholine were reacted accordingto the same procedure as Example 70 to give the title compound (50 mg,Yield 26%).

¹H-NMR (400 HMz, CDCl₃); δ 11.13 (br s, 1H), 7.06 (br s, 1H), 6.93 (s,1H), 6.82 (s, 1H), 6.39 (s, 1H), 4.61 (m, 1H), 3.88 (m, 2H), 3.77 (s,4H), 3.45 (m, 2H), 3.07 (m, 1H), 2.70 (m, 6H), 2.44 (m, 2H), 2.10 (m,3H), 1.95 (m, 1H), 1.71 (m, 2H), 1.64 (m, 2H), 1.54 (m, 2H)

Example 154 Synthesis of3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-one

The compound (150 mg, 0.38 mmol) prepared in Example 149 and1-methylpiperazine instead of morpholine were reacted according to thesame procedure as Example 73 to give the title compound (50 mg, Yield28%).

¹H-NMR (400 HMz, CDCl₃); δ 11.26 (br s, 1H), 6.93 (s, 1H), 6.85 (s, 1H),6.38 (s, 1H), 4.73 (m, 1H), 3.83 (m, 1H), 3.59 (m, 3H), 3.30 (m, 2H),3.14 (m, 1H), 2.45 (m, 4H), 2.30 (m, 5H), 2.04 (m, 4H), 1.70 (m, 4H),1.52 (m, 2H)

Preparation 69: Synthesis of methanesulfonic acid3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propylester

The compound (140 mg, 0.37 mmol) prepared in Example 154 was reactedaccording to the same procedure as Preparation 22 to give the titlecompound (120 mg, Yield 71%).

Example 155 Synthesis of1-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propyl}-piperazin-1-yl)-ethanone

The compound (100 mg, 0.22 mmol) prepared in Preparation 69 was reactedaccording to the same procedure as Example 125 to give the titlecompound (49 mg, Yield 46%).

¹H-NMR (400 HMz, CDCl₃); δ 10.33 (br s, 1H), 6.97 (s, 1H), 6.81 (s, 1H),6.42 (s, 1H), 4.64 (m, 1H), 3.85 (m, 1H), 3.65 (m, 2H), 3.56 (m, 1H),3.45 (m, 2H), 3.13 (m, 1H), 2.43 (m, 6H), 2.04 (m, 2H), 1.72 (m, 8H),1.54 (m, 2H)

Example 156 Synthesis of{5-chloro-2-[(R)-4-(3-morpholin-4-yl-propyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine

The compound (100 mg, 0.22 mmol) prepared in Preparation 69 andmorpholine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 125 to give the title compound (43 mg, Yield44%).

¹H-NMR (400 HMz, CDCl₃); δ 11.07 (br s, 1H), 6.90 (s, 1H), 6.74 (s, 1H),6.36 (s, 1H), 4.61 (m, 1H), 3.94 (m, 4H), 3.55 (m, 1H), 3.04 (m, 3H),2.04 (m, 7H), 1.71 (m, 3H), 1.61 (m, 4H), 1.26 (m, 3H)

Example 157 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.0 g, 8.6 mmol) prepared in Preparation 7 and thecompound (3.4 g, 10.2 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (500 mg, Yield 15%).

¹H-NMR (400 HMz, CDCl₃); δ 10.75 (br s, 1H), 6.82 (d, 2H), 6.32 (s, 1H),4.71 (m, 1H), 4.01 (q, 2H), 3.83 (m, 1H), 3.53 (m, 1H), 3.11 (m, 1H),2.44 (m, 2H), 2.37 (s, 3H), 2.01 (m, 4H), 1.64 (m, 4H), 1.40 (m, 2H)

Example 158 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (300 mg, 0.75 mmol) prepared in Example 157 was dissolvedin tetrahydrofuran (25 ml) and methanol (25 ml). 1N aqueous sodiumhydroxide solution (4.0 ml, 4 mmol) was added thereto, and the mixturewas stirred for 3 h at room temperature. After completion of thereaction, 1N hydrochloric acid was added. The mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give the title compound (235 mg, Yield 84%).

¹H-NMR (400 HMz, CDCl₃); δ 11.34 (br s, 1H), 6.56 (s, 1H), 6.54 (s, 1H),6.06 (s, 1H), 5.05 (br d, 1H), 4.60 (m, 1H), 3.81 (m, 1H), 3.45 (m, 1H),3.06 (m, 1H), 2.28 (s, 3H), 2.09˜1.93 (m, 5H), 1.78-1.54 (m, 7H)

Preparation 70: Synthesis of3-[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.6 g, 8.4 mmol) prepared in Preparation 12 and thecompound (3.4 g, 10.2 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (1.0 g, Yield 25%).

Example 159 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (600 mg, 1.26 mmol) prepared in Preparation 70 was reactedaccording to the same procedure as Example 158 to give the titlecompound (430 mg, Yield 76%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.59 (br s, 1H), 7.29 (m, 2H), 7.01 (m,1H), 6.92 (m, 2H), 6.67 (s, 1H), 6.40 (d, 1H), 6.21 (d, 1H), 5.99 (d,1H), 4.63 (m, 1H), 3.75 (m, 1H), 3.50 (m, 1H), 3.11 (m, 1H), 2.08 (m,2H), 2.03 (m, 1H), 1.90 (m, 2H), 1.81 (m, 1H), 1.71 (m, 2H), 1.56 (m,4H)

Example 160 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.2 g, 8.9 mmol) prepared in Preparation 2 and thecompound (3.6 g, 10.7 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (1.1 g, Yield 31%).

¹H-NMR (400 HMz, CDCl₃); δ 10.48 (br s, 1H), 6.91 (s, 1H), 6.69 (m, 1H),6.30 (m, 1H), 4.77 (m, 1H), 4.19˜4.02 (m, 3H), 3.84 (m, 1H), 3.60 (m,1H), 3.18 (m, 1H), 2.51 (m, 2H), 2.07 (m, 4H), 1.74˜1.46 (m, 6H), 1.21(m, 3H)

Example 161 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (1.0 g, 2.48 mmol) prepared in Example 160 was reactedaccording to the same procedure as Example 158 to give the titlecompound (430 mg, Yield 46%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.63 (br s, 1H), 6.49 (m, 1H), 6.33 (m,1H), 6.09 (m, 1H), 6.66 (m, 1H), 4.61 (m, 1H), 3.85 (m, 1H), 3.52 (m,1H), 3.11 (m, 1H), 2.09˜1.74 (m, 12H),

Example 162 Synthesis of3-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.1 g, 7.01 mmol) prepared in Preparation 6 and thecompound (2.3 g, 6.89 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (530 mg, Yield 16%).

¹H-NMR (400 HMz, CDCl₃); δ 10.02 (br s, 1H), 7.16 (s, 1H), 6.81 (s, 1H),6.57 (s, 1H), 4.74 (m, 1H), 4.11 (m, 2H), 4.02 (m, 2H), 3.59 (q, 1H),3.16 (q, 1H), 2.52 (m, 2H), 2.06 (m, 4H), 1.72 (m, 3H), 1.49 (m, 2H),1.19 (t, 3H)

Example 163 Synthesis of3-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (420 mg, 0.88 mmol) prepared in Example 162 was reactedaccording to the same procedure as Example 158 to give the titlecompound (350 mg, Yield 91%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.77 (br s, 1H), 6.96 (s, 1H), 6.68 (s,1H), 6.31 (m, 1H), 6.29 (s, 1H), 4.64 (m, 1H), 3.82 (m, 1H), 3.53 (m,1H), 3.13 (m, 1H), 2.05 (m, 2H), 1.97 (m, 2H), 1.77 (m, 3H), 1.58 (m,4H)

Preparation 71: Synthesis of3-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (1.64 g, 7.49 mmol) prepared in Preparation 8 and thecompound (3.50 g, 10.46 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (1.23 g, Yield 43%).

Example 164 Synthesis of3-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (1.0 g, 2.59 mmol) prepared in Preparation 71 was reactedaccording to the same procedure as Example 158 to give the titlecompound (560 mg, Yield 60%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.46 (br s, 1H), 6.85 (m, 2H), 6.70 (s,1H), 6.27 (d, J=4.0 Hz, 1H), 5.94 (d, J=8.0 Hz, 1H), 4.65 (m, 1H), 3.86(m, 1H), 3.52 (m, 1H), 3.11 (m, 1H), 2.05 (m, 2H), 1.97 (m, 3H), 1.78(m, 3H), 1.56 (m, 4H)

Preparation 72: Synthesis of3-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.1 g, 8.5 mmol) prepared in Preparation 9 and thecompound (3.4 g, 10.2 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (700 mg, Yield 20%).

Example 165 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (700 mg, 1.69 mmol) prepared in Preparation 72 was reactedaccording to the same procedure as Example 158 to give the titlecompound (430 mg, Yield 66%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.28 (br s, 1H), 6.61 (s, 1H), 6.27 (s,1H), 5.97 (m, 1H), 5.88 (s, 1H), 4.59 (m, 1H), 3.75 (m, 1H), 3.68 (s,3H), 3.48 (m, 2H), 3.08 (m, 1H), 2.00 (m, 5H), 1.75 (m, 3H), 1.57 (m,4H)

Example 166 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.4 g, 9.0 mmol) prepared in Preparation 11 and thecompound (3.0 g, 8.98 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (600 mg, Yield 16%).

¹H-NMR (500 HMz, CDCl₃); δ 9.79 (br s, 1H), 6.80 (s, 1H), 6.44 (s, 1H),6.19 (s, 1H), 4.69 (m, 1H), 4.11 (q, 2H), 4.03 (q, 2H), 3.83 (m, 1H),3.54 (m, 1H), 3.11 (m, 1H), 2.49 (m, 2H), 2.02 (m, 4H), 1.69 (m, 2H),1.60 (m, 2H), 1.48 (m, 2H), 1.25 (t, 3H), 1.19 (t, 3H)

Example 167 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (300 mg, 0.70 mmol) prepared in Example 166 was reactedaccording to the same procedure as Example 158 to give the titlecompound (210 mg, Yield 71%).

¹H-NMR (400 HMz, DMSO-d₆); δ 11.37 (br s, 1H), 6.78 (s, 1H), 6.30 (s,1H), 5.94 (s, 1H), 4.64 (m, 1H), 3.93 (q, 2H), 3.82 (m, 1H), 3.60 (m,1H), 3.21 (m, 1H), 2.44 (m, 2H), 1.97 (m, 4H), 1.71 (m, 2H), 1.57 (m,4H), 1.32 (t, 3H)

Preparation 73: Synthesis of7-nitro-5-trifluoromethoxy-1H-indole-carboxylic acid methyl ester

4-Trifluoromethoxy-2-nitroaniline (10.0 g, 45.0 mmol) was reactedaccording to the same procedures as Preparations 3 to 5 to give thetitle compound (3.0 g, Yield 22%).

Example 168 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester

The compound (2.7 g, 8.96 mmol) prepared in Preparation 73 and thecompound (3.0 g, 8.98 mmol) prepared in Preparation 17 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (900 mg, Yield 21%).

¹H-NMR (500 HMz, CDCl₃); δ 10.97 (br s, 1H), 6.93 (s, 1H), 6.86 (s, 1H),6.30 (s, 1H), 4.76 (m, 1H), 4.05-3.89 (m, 3H), 3.78 (m, 1H), 3.57 (m,1H), 3.16 (m, 2H), 2.42 (m, 2H), 2.00 (m, 4H), 1.63 (m, 2H), 1.45 (m,1H), 1.34 (m, 1H)

Example 169 Synthesis of3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid

The compound (750 mg, 1.60 mmol) prepared in Example 168 was reactedaccording to the same procedure as Example 158 to give the titlecompound (600 mg, Yield 5%).

¹H-NMR (40 HMz, DMSO-d₆) 11.61 (br s, 1H), 6.85 (d, 1H), 6.77 (s, 1H),6.16 (s, 1H), 4.66 (m, 1H), 3.85 (m, 1H), 3.60 (m, 2H), 3.20 (m, 1H),2.42 (m, 2H), 1.99 (m, 4H), 1.71 (m, 2H), 1.58 (m, 4H)

Example 170 Synthesis of[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethoxy]-aceticacid ethyl ester

The compound (50 mg, 0.15 mmol) prepared in Example 5 was dissolved intetrahydrofuran (5 ml). Bromoacetic acid ethyl ester (30 mg, 0.18 mmol)and sodium hydride (8 mg, 0.18 mmol) were added thereto, and the mixturewas stirred for 3 h at room temperature. After completion of thereaction, 1N hydrochloric acid was added. The mixture was extracted withethyl acetate, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give the title compound (15 mg, Yield 24%) and theacid compound (40 mg, Yield 68%) of Example 171.

¹H-NMR (400 HMz, CDCl₃); δ 10.16 (br s, 1H), 6.87 (s, 1H), 6.66 (dd,J=2.4, 9.2 Hz, 1H), 6.30 (dd, J=2.4, 11.8 Hz, 1H), 4.94 (m, 1H), 4.25(q, 2H), 4.13 (d, J=5.6 Hz, 2H), 3.87 (m, 1H), 3.76 (d, J=6.4 Hz, 2H),3.56 (m, 1H), 3.44 (m, 1H), 2.07 (m, 2H), 1.67 (m, 4H), 1.51 (m, 2H),1.30 (t, 3H)

Example 171 Synthesis of[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethoxy]-aceticacid

The title compound was additionally obtained in the process of Example170.

¹H-NMR (400 HMz, DMSO-d₆); δ 12.70 (br s, 1H), 7.07 (s, 1H), 6.57 (d,J=8.8 Hz, 1H), 6.23 (d, J=12 Hz, 1H), 5.13 (m, 1H), 4.34 (m, 1H), 4.07(m, 2H), 3.89 (m, 1H), 3.63 (m, 3H), 2.03 (m, 2H), 1.58 (m, 6H)

Example 172 Synthesis ofcyclopentyl-{2-[(R)-4-(3-cyclopentyl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (140 mg, 0.41 mmol) prepared in Example 42 was dissolved inN,N-dimethylformamide (5 ml). 1,1′-Dicarbonyldiimidazole (73 mg, 0.45mmol) was added thereto, and the mixture was stirred for 30 min at roomtemperature. N-hydroxy-cyclopentanecarboxamidine (260 mg, 2.03 mmol) wasadded thereto, and the mixture was stirred for 5 h at 80° C. Aftercompletion of the reaction, water was added. The mixture was extractedwith ethyl acetate, dried over anhydrous magnesium sulfate, andfiltered. The filtrate was distilled under reduced pressure, andpurified by column chromatography to give the title compound (100 mg,Yield 56%).

¹H-NMR (400 HMz, CDCl₃); δ 10.62 (br s, 1H), 7.04 (d, 1H), 6.97 (t, 1H),6.92 (d, 1H), 6.49 (d, 1H), 5.20 (m, 1H), 3.83 (m, 2H), 3.64 (m, 1H),3.39 (m, 1H), 3.31 (m, 1H), 3.17 (m, 1H), 3.01 (m, 1H), 1.97 (m, 4H),1.73 (m, 4H), 1.60 (m, 6H), 1.46 (m, 2H), 1.34 (m, 2H)

Example 173 Synthesis ofcyclopentyl-{2-[(R)-4-(3-piperidin-1-yl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine

The compound (140 mg, 0.41 mmol) prepared in Example 42 andN-hydroxypiperidinecarboxamidine instead ofN-hydroxycyclopentanecarboxamidine were reacted according to the sameprocedure as Example 172 to give the title compound (100 mg, Yield 54%).

¹H-NMR (400 HMz, CDCl₃); δ 10.56 (br s, 1H), 7.01 (d, 1H), 6.96 (t, 1H),6.90 (d, 1H), 6.46 (d, 1H), 5.23 (m, 1H), 3.83 (m, 2H), 3.64 (m, 1H),3.36 (m, 1H), 3.31 (m, 1H), 3.17 (m, 2H), 3.01 (m, 1H), 1.95 (m, 2H),1.68-1.43 (m, 11H), 1.35 (m, 1H)

Preparation 74: Synthesis of 7-phenoxy-1H-indole-2-carboxylic acidmethyl ester

(Step 1)

3-Phenoxy-benzaldehyde (16.1 g, 81.3 mmol) was dissolved in methanol(300 ml). Sodium methoxide (70.3 g, 25%, 325.3 mmol) and methylazidoacetate (42.0 g, 325.3 mmol) were added thereto, and the mixturewas stirred for 5 h at −10° C. After completion of the reaction, waterwas added. The mixture was extracted with ethyl acetate, dried overanhydrous magnesium sulfate, and filtered. The filtrate was distilledunder reduced pressure, and purified by column chromatography to give anazido compound (18.5 g, Yield 77%).

(Step 2)

The compound (18.5 g, 62.6 mmol) prepared in Step 1 was dissolved inxylene (100 ml), and stirred for 4 h at 120° C. After completion of thereaction, and reaction solution was distilled under reduced pressure,and purified by column chromatography to give the title compound (4.9 g,Yield 29%).

Preparation 75: Synthesis of (R)-3-amino-4-tritylsulfanyl-butyric acidmethyl ester hydrochloride

(Step 1)

L-cysteine hydrochloride (50 g, 284.7 mmol) was dissolved inN,N-dimethylformamide (200 ml). Trityl chloride (119 g, 427.0 mmol) wasadded thereto, and the mixture was stirred for 48 h at room temperature.After completion of the reaction, 10% sodium acetate (1.5 L) was added.The mixture was filtered to give a solid, which was then added toacetone (1.5 L), and stirred for 30 min at 50° C. The insoluble solidwas filtered, and dried to give a trityl compound (80 g, Yield 78%).

(Step 2)

The compound (34 g, 154 mmol) prepared in Step 1 was reacted accordingto the same procedures as Steps 2˜5 of Preparation 15 to give the titlecompound (26 g, Yield 39%).

Preparation 76: Synthesis of[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acidmethyl ester

The compound (4.9 g, 18.3 mmol) prepared in Preparation 74 and thecompound (10.4 g, 24.3 mmol) prepared in Preparation 75 were reactedaccording to the same procedures as Preparation 33, Preparation 34 andExample 26 in the order to give the title compound (4.48 g, Yield 57%).

Example 174 Synthesis of[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid

The compound (500 mg, 1.36 mmol) prepared in Preparation 76 was reactedaccording to the same procedure as Example 27 to give the title compound(300 mg, Yield 63%).

¹H-NMR (400 HMz, DMSO-d₆); δ 12.17 (br s, 1H), 7.51 (d, J=8.0 Hz, 1H),7.41 (t, 1H), 7.28 (br s, 1H), 7.16 (m, 2H), 7.08 (m, 2H), 6.84 (d,J=8.0 Hz, 1H), 4.95 (m, 1H), 3.77 (m, 1H), 3.37 (m, 1H), 2.86 (m, 1H),2.75 (m, 1H)

Preparation 77: Synthesis of2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol

The compound (2.56 g, 6.99 mmol) prepared in Preparation 76 wasdissolved in tetrahydrofuran (20 ml). Lithium borohydride (7 ml, 2.0M inTHF, 14.0 mmol) was added thereto, and the mixture was stirred for 4 hat 0° C. After completion of the reaction, water was added. The mixturewas extracted with ethyl acetate, washed with saturated sodium chloridesolution, dried over anhydrous magnesium sulfate, and filtered. Thefiltrate was distilled under reduced pressure, and purified by columnchromatography to give the title compound (2.20 g, Yield 93%).

Preparation 78: Synthesis of2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-7-phenoxy-1H-indole

The compound (2.20 g, 6.50 mmol) prepared in Preparation 77 was reactedaccording to the same procedure as Preparation 50 to give the titlecompound (1.80 g, Yield 62%).

Example 175 Synthesis of1-(4-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone

The compound (100 mg, 0.22 mmol) prepared in Preparation 78 wasdissolved in acetonitrile (3 ml). 1-Acetylpiperazine (29 mg, 2.2 mmol)and potassium carbonate (93 mg, 0.67 mmol) were added thereto, and themixture was stirred for 8 h at 80° C. After completion of the reaction,water was added. The mixture was extracted with ethyl acetate, washedwith saturated sodium chloride solution, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was distilled under reducedpressure, and purified by column chromatography to give the titlecompound (40 mg, Yield 41%).

¹H-NMR (400 HMz, CDCl₃); δ 9.73 (br s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.41(m, 2H), 7.11 (t, 1H), 7.07 (m, 3H), 6.91 (s, 1H), 6.78 (d, J=8.0 Hz,2H), 4.71 (m, 1H), 3.58 (m, 2H), 3.48 (m, 1H), 3.38 (m, 2H), 3.11 (t,1H), 2.56 (m, 2H), 2.50 (m, 4H), 2.06 (s, 3H), 1.98 (m, 1H), 1.82 (m,1H)

Example 176 Synthesis of2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-7-phenoxy-1H-indole

The compound (100 mg, 0.22 mmol) prepared in Preparation 78 andmorpholine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 175 to give the title compound (40 mg, Yield45%).

¹H-NMR (400 HMz, CDCl₃); δ 9.17 (br s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.34(t, 2H), 7.13 (t, 1H), 7.05 (m, 3H), 6.93 (s, 1H), 6.80 (d, J=8.0 Hz,2H), 4.68 (m, 1H), 3.72 (m, 4H), 3.70 (t, 1H), 3.14 (t, 1H), 2.62 (m,2H), 2.51 (m, 4H), 2.07 (m, 1H), 1.85 (m, 1H)

Example 177 Synthesis of7-phenoxy-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indole

The compound (100 mg, 0.22 mmol) prepared in Preparation 78 andpyrrolidine instead of 1-acetylpiperazine were reacted according to thesame procedure as Example 175 to give the title compound (80 mg, Yield93%).

¹H-NMR (400 HMz, CDCl₃); δ 9.37 (br s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.34(t, 2H), 7.10 (1, 1H), 7.05 (m, 3H), 6.92 (s, 1H), 6.80 (d, J=8.0 Hz,2H), 4.67 (m, 1H), 3.54 (t, 1H), 3.14 (t, 1H), 2.57 (m, 2H), 2.51 (m,4H), 2.07 (m, 1H), 1.89 (m, 1H), 1.77 (m, 4H)

Example 178 Synthesis ofdimethyl-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-amine

The compound (100 mg, 0.22 mmol) prepared in Preparation 78 anddimethylamine instead of 1-acetylpiperazine were reacted according tothe same procedure as Example 175 to give the title compound (70 mg,Yield 87%).

¹H-NMR (400 HMz, CDCl₃); δ 9.31 (br s, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.43(t, 2H), 7.10 (1, 1H), 7.05 (m, 3H), 6.92 (s, 1H), 6.80 (d, J=8.0 Hz,2H), 4.65 (m, 1H), 3.54 (t, 1H), 3.14 (t, 1H), 2.57 (m, 2H), 2.27 (s,6H), 2.04 (m, 1H), 1.85 (m, 1H)

Preparation 79: Synthesis of(S)-3-amino-4-(4-methoxy-benzylsulfanyl)-butyric acid isopropyl ester

(Step 1)

The commercially available (S)-2-BOC-amino-succinic acid 1-methyl ester(2.4 g, 10 mmol) was dissolved in DCM (30 ml), and triethylamine (2.8ml, 20 mmol) was added thereto. Isopropanol (660 mg, 11 mmol), EDC (2.5g, 26 mmol) and HOBt (2.3 g, 30 mmol) were added, and the mixture wasstirred for 4 h at room temperature. The reaction was quenched bysaturated aqueous NaHCO₃ solution. The organic material was extractedwith EtOAc, washed with saturated aqueous sodium chloride solution, anddried over anhydrous magnesium sulfate. The solvent was removed underreduced pressure, and the residue was purified by column chromatographyto give a compound (2.5 g, Yield 87%).

(Step 2)

The compound (57.8 g, 200 mmol) prepared in Step 1 was dissolved inmethanol (200 ml). LiBH₄ (1N THF solution, 400 ml) was added thereto,and the mixture was stirred for 2 h while maintaining the temperature at10° C. or less. After completion of the reaction, the reaction solutionwas cooled to 0° C. Water was slowly added to quench the reaction, andmethanol was removed under reduced pressure. The residue was dilutedwith saturated aqueous NaHCO₃ solution. The organic material wasextracted with EtOAc, and dried over MgSO₄. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography to give a compound (39 g, Yield 75%).

(Step 3)

The compound (36 g, 137.8 mmol) prepared in Step 2 and triethylamine(38.4 ml, 275.5 mmol) were dissolved in dichloromethane (200 ml).Methanesulfonyl chloride (11.7 ml, 151.5 mmol) was added in dropsthereto, and the mixture was stirred for 1 h at 0° C.˜room temperature.After completion of the reaction, 1N hydrochloric acid solution wasadded. The organic material was extracted with ethyl acetate, washedwith saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate to give a compound.

(Step 4)

Sodium hydride (5.5 g, 137.8 mmol) and 4-methoxybenzylmercaptan (15.4ml, 110.2 mmol) were dissolved in N,N-dimethylformamide (150 ml), andthe mixture was stirred for 10 min at 0° C. To the resulting solutionwas added in drops the compound (46.7 g, 137.8 mmol) prepared in Step 3,and the mixture was stirred for 4 h at 0° C.

Water was added thereto to quench the reaction. The organic material wasextracted with ethyl acetate, washed with saturated aqueous sodiumchloride solution, and dried over anhydrous magnesium sulfate. Thesolvent was removed under reduced pressure, and the residue was purifiedby column chromatography to give a compound.

(Step 5)

The compound (24 g, 62.7 mmol) prepared in Step 4 was dissolved indichloromethane (200 ml). 4N hydrochloric acid/ethyl acetate solution(20 ml) was added thereto, and the mixture was stirred for 2 h at roomtemperature. After completion of the reaction, the solvent wasthoroughly removed under reduced pressure. The residue wasrecrystallized from diethylether (150 ml), and dried to give the titlecompound (20 g, Yield 96%).

Examples 179 to 196

Indole carboxylic acids prepared in Preparations 5, 7, 8 and 12 and theamine compound prepared in Preparation 79 were reacted according to thesame procedure as Preparation 34 to give indole derivatives, which werethen reacted with commercially available carbonyl compounds according tothe same procedures as Examples 26 and 27 in the order to give theExample compounds as shown in the following table.

R3 R2′ R1 Example H¹ NMR data 179 carboxyl chloro cyclopentyl (400 mhz,DMSO-d₆, ppm); δ 12.51(br s, 1H), 11.51(s, 1H), 6.79(s, 1H), 6.79(s,1H), 6.16(s, 1H), 6.14(d, 1H), 4.87(m, 1H), 3.80(m, 1H), 3.61(m, 1H),3.19(m, 1H), 2.72(m, 1H), 2.64(m, 1H), 1.93(m, 2H), 1.69(m, 2H), 1.56(m,4H) 180 carboxyl methyl 1-(trifluoroacetyl)piperidin-4-yl (400 MHz,CDCl₃); δ 11.94 (brs, 1H), 6.98 (s, 1H), 6.78 (s, 1H), 6.25 (s, 1H),5.33 (m, 1H), 4.13 (m, 1H), 3.76-3.68 (m, 5H), 3.47-3.41 (m, 3H),2.74-2.63 (m, 2H), 2.36 (s, 3H), 2.04 (m, 2H), 1.56 (m, 2H) 181 carboxylH (tetrahydropyran-2-yl)methyl (400 MHz, CDCl₃); δ 11.68 (brs, 1H),7.06-6.98 (m, 3H), 6.45 (s, 1H), 5.32 (m, 1H), 3.96 (m, 1H), 3.77-3.61(m, 2H), 3.43 (m, 1H), 3.28-3.21 (m, 3H), 2.80 (m, 1H), 2.65 (m, 1H),1.83 (m, 1H), 1.71 (m, 1H), 1.62-1.42 (m, 4H) 182 carboxyl Htetrahydropyran-4-yl (400 MHz, CDCl₃); δ 11.87 (brs, 1H), 7.15 (s, 1H),7.03 (m, 2H), 6.50 (m, 1H), 5.39 (m, 1H), 4.06 (m, 2H), 3.80-3.62 (m,2H), 3.57 (m, 2H), 3.29 (m, 1H), 2.83 (m, 1H), 2.69 (m, 1H), 2.11 (m,2H), 1.64 (m, 2H) 183 carboxyl H (tetrahydropyran-4-yl)methyl (400 MHz,CDCl₃); δ 11.89 (brs, 1H), 7.13 (s, 1H), 7.04 (m, 2H), 6.44 (m 1H), 5.39(m, 1H), 3.98 (m, 2H), 3.77 (m, 1H), 3.41 (m, 2H), 3.25 (m, 1H), 3.13(m, 2H), 2.78 (m, 1H), 2.64 (m, 1H), 2.00 (m, 1H), 1.79 (m, 2H), 1.44(m, 2H) 184 carboxyl methyl 1-acetyl-pyrrolidin-3-yl (400 MHz, CDCl₃); δ10.13 (brs, 1H), 6.93 (s, 1H), 6.82 (s, 1H), 6.38 (s, 1H), 5.09 (m, 1H),4.16 (m, 1H), 3.67 (m, 2H), 3.52 (m, 2H), 3.38 (m, 1H), 3.25 (m, 1H),2.91 (m, 1H), 2.66 (m, 1H), 2.48 (s, 3H), 2.23 (m, 1H), 2.00 (m, 1H) 185carboxyl H cyclopentyl (400 MHz, CDCl₃); δ 11.74 (brs, 1H), 7.06 (s,1H), 6.99 (m, 2H), 6.45 (s, 1H), 5.48 (m, 1H), 3.90 (m, 1H), 3.71 (m,1H), 3.23 (m, 1H), 2.75 (m, 1H), 2.67 (m, 1H), 2.04 (m, 2H), 1.75 (m,2H), 1.61-1.48 (m, 4H) 186 carboxyl phenoxy (tetrahydropyran-4-yl)methyl(400 MHz, CDCl₃); δ 11.95 (brs, 1H), 7.28 (m, 2H), 7.06-6.96 (m, 4H),6,58 (s, 1H), 6.24 (s, 1H), 5.33 (m, 1H), 3.98 (m, 2H), 3.75 (m, 1H),3.58- 3.47 (m, 3H), 2.23 (m, 1H), 2.78-2.62 (m, 2H), 2.04 (m, 2H), 1.26(m, 2H) 187 carboxyl phenoxy tetrahydropyran-4-yl (400 MHz, CDCl₃); δ11.94 (brs, 1H), 7.00 (s, 1H), 6.78 (s, 1H), 6.26 (s, 1H), 5.35 (m, 1H),3.71 (m, 1H), 3.63 (m, 1H), 3.22 (m, 1H), 2.75 (m, 1H), 2.62 (m, 1H),2.37 (s, 3H), 2.25 (m, 1H), 2.09-1.73 (m, 7H) 188 carboxyl chlorotetrahydropyran-4-yl (400 MHz, CDCl₃); δ 11.21(br s, 1H), 6.66(s, 1H),6.61(s, 1H), 6.00(s, 1H), 4.89(br s, 1H), 3.95(m, 1H), 3.63(m, 1H),3.35(m, 2H), 2.67(m, 2H), 2.50(s, 3H), 2.42(m, 2H), 1.80(m, 4H) 189carboxyl methyl cyclobutyl (400 MHz, CDCl₃); δ 11.829 d, 1H), 6.95(s,1H), 6.79(s, 1H), 6.20(d, 1H), 5.30(br s, 1H), 4.15(m, 1H), 4.05~3.75(m,5H), 3.66(m, 1H), 3.19(s, 1H), 2.79~2.61(m, 2H), 2.37(s, 3H), 2.23(m,1H), 1.98(m, 1H) 190 carboxyl methyl tetrahydrofuran-3-yl (400 MHz,CDCl₃/MeOH-d₄); δ 11.24(br s, 1H), 6.84(s, 1H), 6.77(s, 1H), 6.25(s,1H), 5.05(m, 1H), 3.56(m, 1H), 3.15(m, 2H), 3.03(m, 2H), 2.78(m, 1H),2.63(m, 1H), 2.34(s, 3H), 1.23(m, 1H), 1.18(m, 1H), 0.52(m, 2H), 0.24(m,2H) 191 carboxyl methyl cyclopropylmethyl (400 MHz, CDCl₃); δ 11.92(brs, 1H), 6.98(s, 1H), 6.77(s, 1H), 6.22(s, 1H), 6.29(br s, 1H), 3.96(m,2H), 3.70(m, 1H), 3.37(m, 2H), 3.18(m, 1H), 3.08(m, 2H), 2.729 m, 1H),2.56(m, 1H), 2.37(s, 3H), 1.91(m, 1H), 1.75(m, 2H), 1.41(m, 2H) 192carboxyl methyl (tetrahydropyran-4-yl)methyl (400 MHz, DMSO-d₆); δ11.35(br s, 1H), 6.67(s, 1H), 6.61(s, 1H), 6.09(s, 1H), 5.81(br s, 1H),4.90(m, 1H), 3.64(m, 1H), 3.21(m, 1H), 3.05(m, 2H), 2.77~2.69(m, 2H),2.28(s, 3H), s.23(m, 1H), 1.85(m, 2H), 1.65~1.58(m, 4H), 1.32(m, 2H) 193carboxyl methyl tetrahydropyran-4-yl (400 MHz, DMSO-d₆); δ 11.88(br s,!H), b7.09(s, 1H), 7.04(s, 1H), 6.74(s, 1H), 4.94(m, 1H), 3.98(m, 1H),3.73(m, 1H), 3.47(m, 1H), 2.87~2.70(m, 2H), 2.51(s, 3H), 1.93(m, 2H),1.76~1.56(m, 6H) 194 MeO₂C— methyl cyclopentyl (400 MHz, CDCl₃); δ10.66(br s, 1H), 6.82(s, 1H), 6.41(s, 1H), 6.17(s, 1H), 5.08(m, 1H),4.01(m, 2H), 3.80(m, 1H), 3.67(m, 1H), 3.49(s, 3H), 3.20(dd, 1H),2.85(dd, 1H), 2.65(dd, 1H), 2.02(m, 1H), 1.66~1.53(m, 4H), 1.45~1.33(m,5H) 195 carboxyl phenoxy cyclopentyl (400 MHz, DMSO-d₆, Na salt); δ11.85(br s, 1H), 7.31(t, 2H), 7.01(t, 1H), 6.93(d, J = 8 Hz, 2H),6.64(s, 1H), 6.48(d, J = 4 Hz, 1H), 6.39(s, 1H), 5.97(s, 1H), 4.93(m,1H), 3.75(m, 1H), 3.55(t, 1H), 3.20(q, 1H), 2.62(dd, 1H), 2.15(q, 1H),1.90(m, 2H), 1.72(m, 2H), 1.60(m, 4H) 196 carboxyl methyl4,4-difluorocyclohexyl-1-yl (400 MHz, CDCl₃); δ 11.94 (brs, 1H), 7.00(s, 1H), 6.78 (s, 1H), 6.26 (s, 1H), 5.35 (m, 1H), 3.71 (m, 1H), 3.63(m, 1H), 3.22 (m, 1H), 2.75 (m, 1H), 2.62 (m, 1H), 2.37 (s, 3H), 2.25(m, 1H), 2.09-1.73 (m, 7H)

Examples 197 to 222

The intermediate esters for preparing the compounds of Examples 179,185, 186, 192, 193, 195 and 196 and commercially available aminecompounds were reacted according to the same procedures as Example 129,Preparation 50 and Example 71 in the order to give the Example compoundsas shown in the following table.

R3 R2′ R1 Example H¹ NMR data 197 (3S)-3-(amino)pyrrolidin-1- chlorocyclopentyl yl (400 MHz, MeOD); δ 7.51(s, 1H), 7.28(s, 1H), 7.06(s, 1H),4.27(m, 1H), 4.15(m, 1H), 3.95-3.8(m, 5H), 3.67(m, 3H), 3.44(dd, 1H),2.70(m, 1H), 2.40-2.25(m, 3H), 2.10(m, 2H), 1.91(m, 4H), 1.71(m, 2H) 198(3S)-3- chloro cyclopentyl (dimethylaminophenyl)ethylaminopyrrolidin-1-yl (500 Hz, CDCl₃); δ 7.16(t, 1H), 6.89(s, 1H),6.74(s, 1H), 6.61(m, 3H), 6.34(s, 1H), 4.64(m, 1H), 3.86(m, 1H), 3.66(m,2H), 3.51(m, 2H), 3.45-3.25(br s, 2H), 3.25- 3.05(br s, 2H), 3.03(t,1H), 3.05-2.95(br s, 1H), 2.92(s, 6H), 2.38(br s, 1H), 2.05- 1.85(m,5H), 1.80-1.65(m, 4H), 1.58(m, 1H) 199 1-(acetyl)piperazin-4-yl chlorocyclopentyl (500 Hz, CDCl₃); δ 10.17(br s, 1H), 7.00(s, 1H), 6.83(s,1H), 6.43(s, 1H), 4.75(m, 1H), 3.83(m, 2H), 3.58(m, 1H), 3.56(dd, 1H),3.48(m, 1H), 3.32(m, 1H), 3.25(m, 1H), 3.15(dd, 1H), 2.46(m, 2H),2.36(m, 1H), 2.26(m, 2H), 2.20(m, 1H), 2.05(s, 3H), 2.04(m, 2H), 1.96(m,1H), 1.80(m, 1H), 1.66(m, 3H), 1.48(m, 2H) 200 1-(acetyl)piperazin-4-ylchloro H (500 Hz, DMSO); δ 11.70(br s, 1H), 10.41(s, 1H), 7.91(s, 1H),7.78(d, 1H), 7.58(s, 1H), 7.46(s, 2H), 7.36(m, 3H), 7.09(t, 1H), 7.05(s,1H), 6.97(d, 2H), 3.86(s, 2H), 2.90(br s, 2H) 201 2-oxopiperazin-4-ylmethyl tetrahydropyran-4-yl (500 MHz, CDCl₃); δ 11.05 (s, 1H), 7.72 (s,1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 4.71-4.67 (m, 1H),4.03-4.01 (m, 2H), 3.62-3.47 (m, 4H), 3.30-3.20 (m, 2H), 3.15 (d, 2H),3.11-3.08 (m, 1H), 2.59-2.53 (m, 4H), 2.42-2.36 (m, 3H), 2.09-2.04 (m,2H), 1.95-1.92 (m, 1H), 1.84-1.81 (m, 1H), 1.59-1.51 (m, 2H) 202morpholin-4-yl methyl tetrahydropyran-4-yl 400 MHz, CDCl₃); δ 10.91(s,1H), 6.85(s, 1H), 6.83(s, 1H), 6.28(s, 1H), 4.81(m, 1H), 3.96(m, 2H),3.60~3.41(m, 7H), 3.17(, 1H), 2.40(m, 2H), 2.36(s, 3H), 2.29(m, 2H),2.18(m, 2H), 2.04~1.79(m, 4H), 1.39(m, 2H) 203 1-(hydroxymethylcarbonyl)phenoxy cyclopentyl piperazin-4-yl (400 MHz, CDCl₃); δ 10.7 (1H, brs),7.30-7.27 (2H, m), 7.04-6.97 (3H, m), 6.86 (1H, s), 6.62 (1H, d, J = 2.0Hz), 6.28 (1H, d, J = 2.5 Hz), 4.87-4.80 (1H, m), 3.80-3.75 (1H, m),3.59-3.55 (2H, m), 3.49-3.45 (1H, m), 3.18-3.08 (2H, m), 3.03-3.01 (1H,m), 2.47-2.38 (3H, m), 2.24-2.14 (3H, m), 2.05-1.88 (4H, m), 1.84-1.55(8H, m), 1.49-1.39 (2H, m) 204 piperazin-1-yl phenoxy cyclopentyl (400MHz, CDCl₃); δ 7.40-7.36 (4H, m), 7.16-7.12 (1H, m), 7.04-7.02 (2H, m),6.94 (1H, s), 4.20-4.15 (1H, m), 3.99-3.94 (1H, m), 3.91-3.80 (5H, m),3.75-3.63 (6H, m), 3.58-3.48 (1H, m), 2.44-2.40 (2H, m), 2.09-2.07 (2H,m), 1.91-1.89 (4H, m), 1.71- 1.69 (2H, m) 205 1-BOC-piperazin-4-ylphenoxy cyclopentyl (400 MHz, CDCl₃); δ 10.7(1H, s), 7.30-7.26 (2H, m),7.03-6.98 (3H, m), 6.85 (1H, s), 6.62 (1H, d, J = 2.0 Hz), 6.26 (1H, d,J = 2.4 Hz), 4.82-4.77 (1H, m), 3.87 (1H, brs), 3.78-3.74 (1H, m),3.59-3.54 (1H, m), 3.31 (4H, brs), 3.19-3.14 (1H, m), 2.48-2.35 (2H, m),2.26 (1H, brs), 2.17 (1H, brs), 2.03-1.91 (4H, m), 1.84-1.75 (1H, m),1.67- 1.53 (4H, m), 1.45 (9H, s), 1.42-1.35 (1H, m) 206

phenoxy cyclopentyl (400 MHz, CDCl₃); δ 10.9 (1H, brs), 7.32-7.28 (2H,m), 7.05-6.99 (3H, m), 6.90 (1H, s), 6.59 (1H, d, J = 1.6 Hz), 6.29 (1H,d, J = 2.0 Hz), 4.77-4.74 (1H, m), 4.06-3.99 (1H, m), 3.95-3.82 (4H, m),3.62-3.57 (1H, m), 3.18-3.14 (1H, m), 2.87-2.80 (3H, m), 2.77-2.74 (1H,m), 2.00-1.98 (4H, m), 1.69 (2H, brs), 1.60-1.56 (6H, m) 2072-oxopiperazin-4-yl phenoxy cyclopentyl (400 MHz, CDCl₃); δ 10.7 (1H,brs), 7.30-7.26 (2H, m), 7.03-7.00 (3H, m), 6.82 (1H, s), 6.60 (1H, d, J= 2.0 Hz), 3.25 (1H, d, J = 2.0 Hz), 4.74-4.71 (2H, m), 3.83 (1H, brs),3.56-3.52 (1H, m), 3.50-3.26 (2H, m), 3.20-3.10 (2H, m), 2.68-2.61 (4H,m), 2.01-1.86 (4H, m), 1.73-1.58 (8H, m) 208 1-[(tetrahydrofuran-2-phenoxy cyclopentyl yl)carbonyl]piperazin-4-yl (400 MHz, CDCl₃); δ10.67-10.58 (1H, m), 7.30-7.27 (2H, m), 7.04-6.98 (m, 3H), 6.85 (1H, d,J = 1.2 Hz), 6.62 (1H, d, J = 2.0 Hz), 6.27 (1H, brs), 4.84-4.78 (1H,m), 4.58-4.54 (m, 1H), 3.96-3.91 (1H, m), 3.87-3.71 (3H, m), 3.59-3.42(3H, m), 3.19- 3.14 (1H, m), 2.47-2.37 (2H, m), 2.33-2.16 (4H, m),2.07-1.87 (6H, m), 1.83-1.75 (4H, m), 1.68-1.56 (1H, m), 1.49-1.40 (2H,m) 209 1-(pyridin-2-yl)piperazin-4- phenoxy cyclopentyl yl (400 MHz,CDCl₃); δ 10.3 (1H, s), 8.19-8.18 (1H, m), 7.49-7.45 (1H, m), 7.29-7.25(2H, m), 7.03-6.98 (3H, m), 6.85 (1H, s), 6.64-6.60 (3H, m), 6.28 (1H,d, J = 2.4 Hz), 4.82-4.78 (1H, m), 3.79 (1H, brs), 3.60-3.55 (1H, m),3.49-3.45 (4H, m), 3.21-3.17 (1H, m), 2.55-2.41 (6H, m), 1.99 (3H, brs),1.88-1.86 (1H, m), 1.70 (3H, brs), 1.61- 1.47 (3H, m) 2101-(2-fluorophenyl)piperazin- phenoxy cyclopentyl 4-yl (400 MHz, CDCl₃);δ 10.7 (1H, s), 7.29-7.25 (2H, m), 7.07-6.98 (5H, m), 6.95-6.88 (2H, m),6.86 (1H, s), 6.23 (1H, d, J = 1.6 Hz), 6.28(1H, d, J = 1.6 Hz),4.88-4.81 (1H, m), 3.89 (1H, brs), 3.60-3.56 (1H, m), 3.23-3.18 (1H, m),2.99 (4H, brs), 2.54-2.43 (5H, m), 2.04-1.94 (3H, m), 1.98-1.82 (2H, m),1.68-1.37 (6H, m) 211 1-(acetyl)piperazin-4-yl phenoxy cyclopentyl (400MHz, CDCl₃); δ 10.6 (1H, s), 7.31-7.27 (2H, m), 7.04-6.98 (3H, m), 6.84(1H, s), 6.60 (1H, d, J = 2.0 Hz), 6.27 (1H, d, J = 1.6 Hz), 4.77-4.72(1H, m), 4.30 (1H, brs), 3.81 (1H, brs), 3.74 (1H, brs), 3.64-3.55 (2H,m), 3.41 (1H, brs), 3.17-3.10 (2H, m), 2.89 (1H, brs), 2.68-2.63 (3H,m), 2.56-2.48 (2H, m), 2.06 (3H, s), 2.03-1.90 (4H, m), 1.72 (2H, brs),1.60-1.56 (4H, m) 212 (2R)-2- methyl (tetrahydropyran-4-yl)methyl(hydroxymethyl)pyrrolidin- 1-yl (CDCl₃, 400 MHz) δ 10.25 (s, 1H), 6.76(s, 1H), 6.74 (s, 1H), 6.23 (s, 1H), 4.67- 4.58 (m, 2H), 4.16-4.09 (m,1H), 4.00-3.94 (m, 2H), 3.73- 3.68 (m, 1H), 3.50-3.36 (m, 2H), 3.11 (d,2H), 2.99-2.94 (m, 2H), 2.32 (s, 3H), 2.15-2.07 (m, 2H), 2.02-1.92 (m,3H), 1.76-1.73 (m, 2H), 1.42-1.36 (m, 2H), 1.14-1.08 (m, 2H), 0.86-0.81(m, 2H), 0.73-0.68 (m, 2H) 213 (3R)-3- phenoxy cyclopentyl(acetylamino)pyrrolidin-1-yl (500 Hz, CDCl₃); δ 11.45(br s, 1H), 8.14(brs, 1H), 6.90(s, 1H), 6.77(s, 1H), 6.37(s, 1H), 4.83(m, 1H), 4.66(m, 1H),4.05(m, 1H), 3.91(m, 1H), 3.77(m, 1H), 3.62-3.52(m, 2H), 3.13(m, 1H),3.08-3.00(m, 2H), 2.84(m, 1H), 2.43(m, 1H), 2.23(m, 1H), 2.05(m, 4H),2.00(s, 3H), 1.80(m, 2H), 1.71(m, 2H), 1.63(m, 2H) 2144-(benzyl)piperazin-1-yl phenoxy cyclopentyl (500 Hz, CDCl₃); δ7.32-7.24(m, 7H), 7.01(m, 3H), 6.77(s, 1H), 6.59(s, 1H), 6.29(s, 1H),4.71(m, 1H), 3.87(m, 1H), 3.56(dd, 1H), 3.50(s, 2H), 3.08(dd, 1H),2.80(br s, 8H), 2.60(br s, 2H), 2.11-1.99(m, 4H), 1.80(m, 2H), 1.71(m,2H), 1.61(m, 2H) 215 morpholin-4-yl methyl (tetrahydropyran-4-yl)methyl(500 MHz, CDCl₃); δ 11.13 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 6.24 (s,1H), 4.81- 4.78 (m, 1H), 3.87 (d, 2H), 3.60-3.46 (m, 5H), 3.35-3.30 (m,2H), 3.19-3.17 (m, 1H), 3.01 (br, 2H), 2.38-2.36 (m, 7H), 2.14 (br, 2H),1.91-1.88 (m, 1H), 1.75-1.71 (m, 2H), 1.28-1.21 (m, 2H) 216morpholin-4-yl phenoxy (tetrahydropyran-4-yl)methyl (400 MHz, CDCl₃); δ10.19 (brs, 1H), 7.29 (m, 2H), 7.01(m, 3H), 6.84(d, 1H), 6.65(d, 1H),6.27(d, 1H), 4.77(m, 1H), 3.93(m, 2H), 3.83(m, 1H), 3.63-3.55(m, 6H),3.35(m, 6H), 3.19(m, 1H), 3.04(m, 2H), 2.46 (m, 2H), 2.34(m, 4H),2.00(m, 1H), 1.83(m, 2H), 1.60(m, 2H), 1.30(m, 2H) 2172-oxopiperazin-4-yl phenoxy (tetrahydropyran-4-yl)methyl (400 MHz,CDCl₃); δ 10.7 (brs, 1H), 7.28(m, 2H), 7.00(m, 3H), 6.85(brs, 1H),6.81(d, 1H), 6.60(d, J = 1.6 Hz, 1H), 6.20(d, J = 2.0 Hz, 1H), 5.03(m,1H), 4.70(m, 1H), 3.98(m, 2H), 3.56(m, 1H), 3.49-3.36(m, 6H),3.15-3.06(m, 4H), 2.80 (m, 1H), 2.71(m, 3H), 1.95-1.91(m, 3H), 1.72(m,2H), 1.42(m, 2H). 218 pyrrolidin-1-yl phenoxy cyclopentyl (500 MHz,CDCl₃); δ 7.31-7.27 (2H, m), 7.03-7.00 (1H, m), 6.96-6.94 (2H, m), 6.50(1H, d, J = 2.0 Hz), 6.17 (1H, d, J = 2.0 Hz), 4.73-4.66 (1H, m), 3.86(brs, 1H), 3.74-3.58 (2H, m), 3.46-3.37 (4, m), 3.23-3.19 (1H, m),2.24-2.10 (6, m), 2.10-1.80 (2H, m), 1.70-1.65 (5H m) 219 morpholin-4-ylH 4,4-difluorocyclohexyl-1-yl (400 MHz, CDCl₃); δ 9.67 (brs, 1H),6.87(s, 1H), 6.82(s, 1H), 6.34 (s, 1H), 4.71 (m, 1H), 3.65( m, 6H), 3.55(dd, J = 8 Hz, 1H), 3.51(m, 1H), 3.15(dd, J = 8 Hz, 1H), 2.52- 2.29(m,9H), 2.15-2.04(m, 4H), 1.96-1.90(m, 2H), 1.58-1.51(m, 2H) 220

phenoxy (tetrahydropyran-4-yl)methyl (500 MHz, CDCl₃); δ 9.47(br s, 1H),6.88(s, 1H), 6.47(s, 1H), 6.39(s, 1H), 5.87(br s, 1H), 4.12-4.00(m, 2H),3.85(br s, 4H), 3.66(m, 1H), 3.58(t, 2H), 3.08(br s, 4H), 2.95(m, 1H),2.85-2.70(m, 3H), 2.41(s, 3H), 2.10(m, 2H), 1.96(m, 2H), 1.60(m, 2H) 2212-oxopiperazin-4-yl phenoxy (tetrahydropyran-4-yl)methyl (500 MHz,CDCl₃); δ 11.03(s, 1H), 8.19(br s, 1H), 6.82(s, 1H), 6.79(s, 1H),6.31(s, 1H), 4.84-4.65(m, 3H), 4.24(m, 1H), 3.91(m, 2H), 3.82-3.55(m,4H), 3.31(m, 2H), 3.19(m, 1H), 3.14(m, 2H), 2.95(m, 2H), 2.69(m, 1H),2.20(m, 1H), 1.98(m, 1H), 1.81(d, 2H), 1.39(m, 2H) 2222-oxopiperazin-4-yl phenoxy 4,4-difluorocyclohexyl-1-yl (400 MHz,CDCl₃); δ 10.14 (brs, 1H), 6.82 (s, 1H), 6.80 (s, 1H), 6.31 (s, 1H),4.65 (m, 1H), 3.54 (m, 1H), 3.53 (dd, J = 8 Hz, 1H), 3.39 (m, 2H), 3.30(m, 1H), 3.22-3.08 (m, 4H), 2.78-2.65 (m, 4H), 2.38 (s, 3H), 2.28-2.04(m, 4H), 1.96-1.86 (m, 2H), 1.73 (m, 2H)

The compounds according to the present invention were tested in theenzyme and animal model experiments in the following Experiments 1 and 2to evaluate their efficacies.

Experiment 1: Glucokinase Enzymatic Activity Assay

Glucokinase known as hexokinase IV (human GK isoform 1, pancreas formand human GK isoform 2, liver form) was cloned into an expression vectorpET15 fx (Novagen Co.), transformed to E. coli BL21 (DE3) (InvitrogenCo.) strain, expressed, and purified using a nickel column Then, theglucokinase obtained from dialysis was used in the following assay.

Glucokinase assay was performed by measuring absorbance according to theconventional manner. Briefly speaking, glucokinase converts thesubstrate glucose to glucose-6-phosphate under certain conditions, andglucose-6-phosphate dehydrogenase irreversibly convertsglucose-6-phosphate to gluconate-6-phosphate. During this procedure,NADH is formed, and its absorbance is measured to calculate theenzymatic activity.

In the measurement of the enzymatic activity, each compound was dilutedby two-fold from the maximum to the minimum concentrations, and 2 μl ofeach solution was added to 96 well UV plate (BD bioscience). 60 μl ofthe first mixture (final concentrations 25 mM Hepes, 25 mM KCl, 2 mMMgCl₂, 1 mM DTT) was added, and thoroughly mixed. 38 μl of the enzymemixture (final concentrations 1 mM ATP, 1 mM NAD, 5 mM glucose, 0.85 UG6PDH, 37 nM GK) was added (final volume 100 μl), and the mixture wasreacted for 10 min at room temperature. The absorbance of NADH wasmeasured at 340 nm using a UV spectrometer (Molecular Device).

The enzyme activating abilities of the compounds according to thepresent invention are represented as AC_(1.5) (the compoundconcentration at which the enzymatic activity is increased by 1.5 times,nM), which is in the range of 0.001 uM to 30 uM or less, preferably0.001 uM to 10 uM, more preferably 0.001 uM to 1 uM. The enzymeactivating abilities of the representative compounds are shown in Table1.

TABLE 1 Example Example Example AC_(1.5) Example compound AC_(1.5) (nM)compound AC_(1.5) (nM) compound (nM) compound AC_(1.5) (nM) 1 22 2 41 3184 4 217 5 7 6 31 7 7 8 32 9 24 10 6 11 14 12 25 13 12 14 8 15 400 1664 21 16 22 112 23 19 24 32 26 7 27 4 28 8 32 22 30 28 31 16 32 18 36 534 11 35 6 36 12 40 3 38 18 39 6 40 17 41 17 46 96 47 27 48 9 49 35 5028 51 167 52 20 53 97 54 18 55 29 56 17 57 21 58 14 59 28 60 29 61 11 6236 63 119 64 17 65 23 69 64 70 32 71 31 72 51 73 25 74 14 75 21 76 14 7727 78 25 79 19 80 21 81 6 82 22 83 45 84 27 85 18 86 23 87 10 88 19 8932 90 37 91 72 92 112 93 239 94 15 95 11 96 5 97 6 98 7 99 5 100 11 10110 102 7 103 16 104 13 105 6 106 14 107 63 108 15 109 26 110 30 111 11112 81 121 40 122 60 123 62 124 24 125 23 126 20 127 21 128 16 129 67130 14 131 10 132 13 137 23 138 36 139 38 140 52 141 24 142 85 143 37144 122 145 138 146 29 147 52 148 12 149 12 150 10 151 14 152 14 153 12154 14 155 12 156 22 157 24 158 16 159 17 160 12 161 10 162 21 163 5 16425 165 12 166 43 167 28 168 15 169 9 170 12 171 23 176 178 173 114 17821 175 71 180 56

Experiment 2: Blood Glucose Lowering Abilities of Glucokinase ActivatorsAfter their Single Oral Administration in Male C57BL/6 Mouse

The glucokinase activators according to the present invention wereorally administered in a single dose in the amount of 30 mg/kg bodyweight to male C57BL/6 mice for 24 h. The media were selected dependingon their solubilities from distilled water, pH 1.2 HCl buffer solution,0.5% methyl cellulose distilled water solution, 10% Gelucire/pH 1.2 HClbuffer solution (1/1). The glucokinase activators were dissolved in theselected media to the medium volume of 0.1 ml/10 g body weight on thebasis of the body weight measured on the day of experiment.

Blood glucose was measured by cutting the tail vein before 1 h (time=−1)from the measurement of blood glucose, collecting blood from the tailvein at immediately before the administration of the glucokinaseactivator (time=0), and at 1, 2, 4, 8, 12, 24 h after administration,loading on the automatic glucometer (Accu-Chek® Active, Roche, USA),dropping 5 μl of the blood to a yellow pad of the Accu-Chek® Activeglucose strip, and recording the measured value.

Mice involved in the experiment were divided into groups (n=10, in thecase of media group n=4) on one day before the experiment so that eachgroup has uniform average and standard deviation for blood glucose after4 hour fasting. Mice were fed ad libitum.

Blood glucose-area under the curve (AUC) with respect to the mediacontrol was calculated for 24 h after administration of the glucokinaseactivators. The blood glucose lowering abilities in % of therepresentative compounds with respect to the 100% of media control wereshown in the following Table 2.

TABLE 2 Hypoglycemic Example ability compound (% medium) Medium 27 75%Distilled water 33 81% Distilled water 37 67% Distilled water 38 71%0.5% Methyl cellulose distilled water solution 42 57% Distilled water 5262% Distilled water 54 52% Distilled water 61 54% Distilled water 96 81%Distilled water 99 72% Distilled water 158 66% Distilled water 159 63%Distilled water 164 73% Distilled water 167 64% Distilled water 174 51%Distilled water

1. Indole compounds of the following formula (1):

in which X represents O or NH, n denotes a number of 0 to 3, Yrepresents a direct bond, —(CH₂)_(p)O—, —(CH₂)_(q)—, or —(CH₂)_(q)SO₂—,p denotes a number of 0 to 2, q denotes a number of 1 to 3, R1represents hydrogen, —(CR4R5)_(p)-A-R6 or —(CR4R5)_(q)—R6, p and q areas defined above, R4 and R5 independently of one another representhydrogen or C₁-C₅-alkyl, A represents 6˜12 membered aryl or optionallyoxo-containing C₃-C₈-cycloalkyl, or represents 3˜10 memberedheterocyclyl or heteroaryl each of which has 1 to 3 hetero atomsselected from O, S, and N, R6 represents hydrogen, hydroxy, halogen,nitro, C₁-C₆-alkylcarbonyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxycarbonyl orcarboxy, R2 represents hydrogen, nitro, halogen, C₁-C₆-alkyl ortrifluoromethyl, represents 5˜12 membered heteroaryl or heterocyclyleach of which has 1 to 3 hetero atoms selected from N and O, orrepresents optionally C₁-C₆-alkylsulfonyl-substituted 6˜12 memberedaryl, R3 represents R7-X—B—X′—, B represents a direct bond, orrepresents 3˜10 membered heterocyclyl or heteroaryl each of whichoptionally contains oxo, is optionally fused, and has 1 to 4 heteroatoms selected from N, O and S, X and X′ independently of one anotherrepresent a direct bond, or are selected from the group consisting of—CO—, —(CH₂)_(q)—, —NR4C(O)—, —NR4-, —OC(O)—, —O—, —(CH₂)_(p)C(O)—,—(CH₂)_(p)O—, —(CH₂)_(p)NR4-, —C(O)NR4- and —S(O)_(r)—, wherein p and qare as defined above, r denotes a number of 0 to 2, and R4 representshydrogen or C₁-C₅-alkyl, R7 represents hydrogen, hydroxy, C₁-C₆-alkyl,C₁-C₆-alkoxy, halogeno-C₁-C₆-alkyl or C₃-C₆-cycloalkyl, represents 6˜12membered aryl, or represents 4˜8 membered heteroaryl or heterocyclyleach of which has 1 to 4 hetero atoms selected from N and O, wherealkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl may beoptionally substituted, and the substituents are one or more selectedfrom the group consisting of hydroxy, halogen, nitrile, amino,C₁-C₆-alkylamino, di(C₁-C₆-alkyl)amino, C₁-C₆-alkyl,halogeno-C₁-C₆-alkyl, C₁-C₆-alkylsulfonyl, aryl-C₁-C₆-alkoxy and oxo,pharmaceutically acceptable salts or isomers thereof.
 2. The compoundsof claim 1 wherein X represents O or NH, n denotes a number of 0 to 3, Yrepresents a direct bond, —(CH₂)_(p)O—, —(CH₂)_(q)—, or —(CH₂)_(g)SO₂—,p denotes a number of 0 to 2, q denotes a number of 1 to 3, R1represents —(CR4R5)_(p)-A-R6 or —(CR4R5)_(q)—R6, p and q are as definedabove, R4 and R5 independently of one another represent hydrogen orC₁-C₅-alkyl, A represents 6˜12 membered aryl or optionallyoxo-containing C₃-C₇-cycloalkyl, or represents 4˜8 membered heterocyclylor heteroaryl each of which has 1 to 3 hetero atoms selected from O, S,and N, R6 represents hydrogen, hydroxy, halogen, nitro,C₁-C₆-alkylcarbonyl C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxycarbonyl orcarboxy, R2 represents hydrogen, halogen, C₁-C₆-alkyl ortrifluoromethyl, represents 5˜8 membered heteroaryl or heterocyclyl eachof which has 1 to 3 hetero atoms selected from N and O, or representsoptionally C₁-C₆-alkylsulfonyl-substituted 6˜10 membered aryl, R3represents R7-X—B—X′—, B represents a direct bond, or represents 4˜10membered heterocyclyl or heteroaryl each of which optionally containsoxo, is optionally fused, and has 1 to 4 hetero atoms selected from N, Oand S, X and X′ independently of one another represent a direct bond, orare selected from the group consisting of —CO—, —(CH₂)_(q)—, —NR4C(O)—,—NR4-, —OC(O)—, —O—, —(CH₂)_(p)C(O)—, —C(O)NR4- and —S(O)_(r)—, whereinp and q are as defined above, r denotes a number of 0 to 2, and R4represents hydrogen or C₁-C₅-alkyl, and R7 represents hydrogen, hydroxy,C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl or C₃-C₆-cycloalkyl, represents 6˜12membered aryl, or represents 4˜8 membered heteroaryl or heterocyclyleach of which has 1 to 4 hetero atoms selected from N and O.
 3. Thecompounds of claim 2 wherein R1 represents —(CH₂)_(p)-A-R6 or—(CR4R5)_(q)—R6, wherein p denotes a number of 0 to 2, q denotes anumber of 1 to 3, R4 and R5 independently of one another representhydrogen or C₁-C₅-alkyl, A represents 6˜12 membered aryl or optionallyoxo-containing C₃-C₆-cycloalkyl or represents 5˜6 membered heterocyclylwhich has 1 to 2 hetero atoms selected from O, S, and N, and R6represents hydrogen, halogen, nitro, C₁-C₆-alkylcarbonyl,C₁-C₆-alkylsulfonyl, C₁-C₆-alkoxycarbonyl or carboxy.
 4. The compoundsof claim 3 wherein R1 is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, difluorocyclohexyl,tetrahydrofuran, tetrahydropyran, (tetrahydropyran-4-yl)methyl,tetrahydrothiopyran, 4-oxo-cyclohexyl, (1-methanesulfonyl)pyrrolidine,(1-acetyl)piperidine, 4-nitrophenyl and methylpropiolate.
 5. Thecompounds of claim 2 wherein Y represents a direct bond, —O—, —(CH₂)O—,—(CH₂)— or —(CH₂)SO₂—.
 6. The compounds of claim 2 wherein R2 representshydrogen, halogen, C₁-C₃-alkyl or trifluoromethyl, represents 5˜6membered heteroaryl or heterocyclyl each of which has 1 to 3 heteroatoms selected from N and O, or represents optionallymethanesulfonyl-substituted 6˜10 membered aryl.
 7. The compounds ofclaim 6 wherein R2 is selected from the group consisting of hydrogen,fluoro, chloro, bromo, methyl, ethyl, propyl, phenyl,methanesulfonylphenyl, pyridine, morpholine, 1,2-imidazole,1,3-imidazole, pyrrolidine and pyrrole.
 8. The compounds of claim 2wherein B represents a direct bond, represents pyrazole, imidazole oroxadiazole each of which is optionally substituted by C₁-C₆-alkyl, orrepresents 5˜9 membered heterocyclyl which optionally contains oxo, isoptionally fused, and has 1 to 4 hetero atoms selected from N, S and O.9. The compounds of claim 8 wherein B represents a direct bond, or isselected from the following formulae (i) to (xi)

in which R7 is as defined in claim 1 or
 2. 10. The compounds of claim 2wherein X′ represents a direct bond, or is selected from the groupconsisting of —CO—, —NR4CO—, —SO₂— and —O—.
 11. The compounds of claim 2wherein X represents a direct bond, or is selected from the groupconsisting of —C(O)NR4-, —NR4-, —OC(O)—, —NR4C(O)—, —(CH₂)C(O)—, —S(O)₂—and —C(O)—.
 12. The compounds of claim 11 wherein X represents a directbond, or is selected from the group consisting of —C(O)NH—, —C(O)N(Me)-,—NH—, —N(Me)-, —OC(O)—, —N(Me)C(O)—, —(CH₂)C(O)—, —S(O)₂— and —C(O)—.13. The compounds of claim 2 wherein R7 represents hydrogen, hydroxy,C₁-C₆-alkyl, halogeno-C₁-C₆-alkyl or C₄-C₆-cycloalkyl, representsoptionally halogen-substituted 6˜10 membered aryl, or represents 5˜6membered heteroaryl or heterocyclyl each of which has 1 to 4 heteroatoms selected from N and O.
 14. The compounds of claim 13 wherein R7 isselected from the group consisting of hydrogen, hydroxy, methyl,trifluoromethyl, ethyl, t-butyl, cyclohexyl, pyrrolidine, phenyl,2-fluorophenyl, piperidine, pyridine, 1,3-pyrazine, 1,4-pyrazine, furan,trifluoromethyl, 1,2,3,4-tetrazole and tetrahydrofuran.
 15. Thecompounds of claim 2 which are selected from the group consisting of[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-methanol;{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;{(R)-2-[7-(tetrahydro-furan-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;{(R)-2-[7-(1-methanesulfonyl-pyrrolidin-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;{(R)-2-[5-chloro-7-(tetrahydro-thiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;Cyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine;Cyclopentyl-[2-((R)-4-morpholin-4-ylmethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine;Cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-7-yl]-amine;{(R)-2-[5-morpholin-4-ylmethyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;[(R)-2-[7-cyclopentylamino-5-pyrazol-1-ylmethyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl]-methanol;[(R)-2-(7-cyclopentylamino-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;{(R)-2-[7-cyclopentylamino-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-methanol;[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol;[7-Cyclopentylamino-2-((R)-4-hydroxymethyl-4,5-dihydro-thiazol-2-yl)-1H-indol-5-yl]-methanol;[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester;[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-ethanol;{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester;{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;2-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]-ethanol;{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;2-{(R)-2-[5-bromo-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester;2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester;2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanol;[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester;[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid ethyl ester;{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester;{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-propoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;{(R)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester;{(R)-2-[7-cyclopentylamino-5-(pyridin-3-yloxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid methyl ester;{(R)-2-[5-(pyridin-3-yloxy)-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester;[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;{(R)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(R)-2-[5-methyl-7-(4-oxo-cyclohexylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(R)-2-[7-cyclopentylamino-5-(4-methanesulfonyl-phenoxy)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester;[(R)-2-(7-cyclopentylamino-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;[(R)-2-(7-cyclopentylamino-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]aceticacid methyl ester;[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methyl ester;[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol;Cyclopentyl-{5-methanesulfonylmethyl-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;1-(4-{2-[(R)-2-(7-cyclopentylamino-5-methanesulfonylmethyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(3-morpholin-4-yl-propyl)-acetamide;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N,N-dimethyl-acetamide;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-ethanone;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(3-dimethylamino-pyrrolidin-1-yl)-ethanone;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(3-hydroxy-pyrrolidin-1-yl)-ethanone;2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-piperidin-1-yl-ethanone;2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-N-methyl-acetamide;2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-1-morpholin-4-yl-ethanone;2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-ethanone;2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-acetamide;1-(4-Acetyl-piperazin-1-yl)-2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanone;2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide;2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone;2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-ethyl-acetamide;2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-methyl-acetamide;2-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-morpholin-4-yl-ethanone;N-methyl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetamide;1-Morpholin-4-yl-2-{(R)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethanone;{5-Chloro-2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;{5-Chloro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;(5-Chloro-2-{(R)-4-[2-(4-ethanesulfonyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;(5-Chloro-2-{(R)-4-[2-(4-methyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperidin-4-ol;(4-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one;(5-Chloro-2-{(R)-4-[2-(3-dimethylamino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;{5-Chloro-2-[(R)-4-(2-piperidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;(5-Chloro-2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;{5-Chloro-2-[(R)-4-(2-pyrazol-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;(S)-1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidine-2-carboxylicacid;{5-Chloro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylicacid ethyl ester;3-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-5-methyl-3H-imidazole-4-carboxylicacid;1-{2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-2-one;1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylicacid;1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperidine-3-carboxylicacid dimethylamide;[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-carbamicacid t-butyl ester;(2-{(R)-4-[2-((S)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;N—[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-pyrrolidin-3-yl]-acetamide;{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone;1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-tetrazol-1-yl-ethanone;1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-3,3,3-trifluoro-propan-1-one;[4-(2-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-furan-2-yl-methanone;(5-Chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;(5-Chloro-2-{(R)-4-[2-(4-pyrimidin-2-yl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;{2-[(R)-4-(2-amino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-cyclopentyl-amine;1-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;Cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-amine;Cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;Cyclopentyl-(2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-1H-indol-7-yl)-amine;4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one;1-(4-{2-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;Cyclopentyl-{5-fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-5-fluoro-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;{5-Fluoro-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;{5-Fluoro-2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl-piperazin-1-yl)-ethanone;(2-{(R)-4-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)-amine;(5-Fluoro-2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-(tetrahydro-pyran-4-yl)-amine;4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one;1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-2-hydroxy-ethanone;Cyclopentyl-{2-[(R)-4-(2-methoxy-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;Cyclopentyl-{2-[(R)-4-(2-dimethylamino-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;Cyclopentyl-{2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;Cyclopentyl-{2-[(R)-4-(2-piperidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;{2-[(R)-4-(2-methanesulfonyl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;1-(4-{2-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;2-Hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-1-yl]-ethanone;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propan-1-ol;3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propionicacid;3-{(R)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-propan-1-ol;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-N-(2-morpholin-4-yl-ethyl)-propionamide;3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-one;1-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propyl}-piperazin-1-yl)-ethanone;{5-Chloro-2-[(R)-4-(3-morpholin-4-yl-propyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine;3-[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester;3-[(R)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester;3-[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester;3-[(R)-2-(5-bromo-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(7-cyclopentylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester;3-[(R)-2-(7-cyclopentylamino-5-ethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid ethyl ester;3-[(R)-2-(7-cyclopentylamino-5-trifluoromethoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-propionicacid;[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethoxy]-aceticacid ethyl ester;[(R)-2-(7-cyclopentylamino-5-fluoro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-ylmethoxy]-aceticacid;Cyclopentyl-{2-[(R)-4-(3-cyclopentyl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;Cyclopentyl-{2-[(R)-4-(3-piperidin-1-yl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid;1-(4-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;2-[(R)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-7-phenoxy-1H-indole;7-Phenoxy-2-[(R)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indole;Dimethyl-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-amine;[(S)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;{(S)-2-[7-(1-acetyl-piperidin-4-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;((S)-2-{7-[(tetrahydro-pyran-2-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-aceticacid;((S)-2-{7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-aceticacid;{(S)-2-[7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(S)-2-[7-(1-acetyl-pyrrolidin-3-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;[(S)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-aceticacid;{(S)-2-[5-phenoxy-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(S)-2-[5-chloro-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;[(S)-2-(7-cyclobutylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;{(S)-2-[5-methyl-7-(tetrahydro-furan-3-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;{(S)-2-[7-(cyclopropylmethyl-amino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;((S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-aceticacid;{(S)-2-[5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;[(S)-2-(7-cyclopentylamino-5-methyl-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid methylester;[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-aceticacid;{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-aceticacid;(2-{(S)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-chloro-1H-indol-7-yl)-cyclopentyl-amine;(5-Chloro-2-{(S)-4-[2-((R)-3-dimethylamino-pyrrolidin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-cyclopentyl-amine;1-(4-{2-[(S)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;1-(4-{2-[(S)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;1-(4-{2-[(S)-2-(5-methyl-7-(tetrahydro-pyran-4-ylamino)-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;{5-Methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-yl)-amine;1-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-2-hydroxy-ethanone;Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-amine;4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazine-1-carboxylicacid t-butyl ester;Cyclopentyl-(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-phenoxy-1H-indol-7-yl)-amine;4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-2-one;(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-(tetrahydro-furan-2-yl)-methanone;Cyclopentyl-(5-phenoxy-2-{(S)-4-[2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-1H-indol-7-yl)-amine;Cyclopentyl-[2-((S)-4-{2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-ethyl}-4,5-dihydro-thiazol-2-yl)-5-phenoxy-1H-indol-7-yl)-amine;1-(4-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-piperazin-1-yl)-ethanone;{(R)-1-[2-[(S)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl]-ethyl]-pyrrolidin-2-yl}-methanol;N—((R)-1-{2-[(S)-2-(7-cyclopentylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethyl}-pyrrolidin-3-yl)-acetamide;(2-{(S)-4-[2-(4-benzyl-piperazin-1-yl)-ethyl]-4,5-dihydro-thiazol-2-yl}-5-phenoxy-1H-indol-7-yl)-cyclopentyl-amine;{5-Methyl-2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)methyl-amine;{2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-5-phenoxy-1H-indol-7-yl}-(tetrahydro-pyran-4-ylmethyl)-amine;4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one;Cyclopentyl-{5-phenoxy-2-[(S)-4-(2-pyrrolidin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-amine;(4,4-Difluoro-cyclohexyl)-{2-[(S)-4-(2-morpholin-4-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl)-amine;(2-{(S)-4-[2-(3-methyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-pyrazin-7-yl]-ethyl)-4,5-dihydro-thiazol-2-yl}-5-phenoxy-1H-indol-7-yl)-(tetrahydro-pyran-4-ylmethyl)-amine;4-[2-((S)-2-{5-phenoxy-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-ethyl]-piperazin-2-one;and4-(2-{(S)-2-[7-(4,4-difluoro-cyclohexylamino)-5-phenoxy-7-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-ethyl)-piperazin-2-one.16. A pharmaceutical composition for the activation of glucokinase,which comprises the compounds of formula (1) as defined in claim 1,pharmaceutically acceptable salts or isomers thereof as an activeingredient together with pharmaceutically acceptable carriers.
 17. Thecomposition of claim 16 for the prevention or treatment of diabetes,complications of diabetes, diabetes related diseases, or obesity. 18.The composition of claim 17 wherein diabetes is type 1 diabetes.
 19. Thecomposition of claim 17 wherein diabetes is type 2 diabetes.
 20. Thecomposition of claim 17 wherein complications of diabetes are neurogenicdisease, hyperlipidemia, hypertension, retinosis, or renal failure. 21.The composition of claim 16 which is a hypoglycemic composition.
 22. Aprocess for preparing a pharmaceutical composition for the prevention ortreatment of the diseases caused by deactivation of glucokinase, whichcomprises the step of mixing the compounds of formula (1) as defined inclaim 1, pharmaceutically acceptable salts or isomers thereof as anactive ingredient together with pharmaceutically acceptable carriers.